farmacocinética corticoide.pdf - UFF

Clin Pharmacokinet 2005; 44 (1): 61-98
REVIEW ARTICLE 0312-5963/05/0001-0061/$34.95/0
© 2005 Adis Data Information BV. All rights reserved.
Pharmacokinetics and
Pharmacodynamics of Systemically
Administered Glucocorticoids
David Czock, Frieder Keller, Franz Maximilian Rasche and Ulla Häussler
Division of Nephrology, University Hospital Ulm, Ulm, Germany
Contents
Abstract .....................................................................................62
1. Pharmacokinetics .........................................................................63
1.1 General ..............................................................................63
1.1.1 Absorption and Distribution ......................................................63
1.1.2 Metabolism and Excretion .......................................................66
1.2 Selected Examples ....................................................................66
1.2.1 Cortisol, Cortisone, and Hydrocortisone ...........................................66
1.2.2 Prednisolone and Prednisone .....................................................66
1.2.3 Methylprednisolone .............................................................67
1.2.4 Dexamethasone ................................................................67
1.3 Pharmacokinetic Drug-Drug Interactions ................................................68
1.3.1 Influence of Other Drugs on Glucocorticoid Pharmacokinetics ......................68
1.3.2 Influence of Glucocorticoids on the Pharmacokinetics of Other Drugs ................69
1.3.3 Interactions Between Glucocorticoids and Ciclosporin, Tacrolimus or Sirolimus
(Rapamycin) ...................................................................69
1.4 Influence of Diseases on Glucocorticoid Pharmacokinetics ...............................70
2. Genomic and Nongenomic Mechanisms of Glucocorticoid Effects ............................71
2.1 Genomic Mechanisms ................................................................71
2.1.1 Glucocorticoid Receptors ........................................................71
2.1.2 Glucocorticoid Response Elements ...............................................71
2.1.3 Transcription Factors (Nuclear Factor κB and Activator Protein 1) ....................73
2.1.4 Post-Transcriptional and Translational Mechanisms ..................................73
2.2 Nongenomic Mechanisms .............................................................73
2.2.1 Specific Nongenomic Mechanisms ...............................................74
2.2.2 Nonspecific Nongenomic Mechanisms ............................................75
3. The Host Defence Response and the Effects of Glucocorticoids ...............................75
3.1 Molecular Mechanisms ................................................................75
3.1.1 Cytokines and Chemokines ......................................................76
3.1.2 Inflammatory Enzymes ...........................................................76
3.2 Cellular Mechanisms ..................................................................76
3.2.1 Cell Trafficking and Adhesion Molecules ...........................................76
3.2.2 T Cell Differentiation .............................................................76
3.2.3 Cell Proliferation ................................................................77
3.2.4 Apoptosis ......................................................................77
3.2.5 Basement Membranes ...........................................................77
3.3 Inflammation .........................................................................77

62 Czock et al.
3.4 Immune Response ....................................................................78
4. Adverse Effects of Glucocorticoids ..........................................................78
5. Pharmacodynamics of Glucocorticoids .....................................................79
5.1 Biomarker and Surrogate Endpoints .....................................................79
5.2 Potency .............................................................................79
5.3 Clinical Efficacy ......................................................................80
5.4 Pharmacodynamic Drug-Drug Interactions ..............................................81
6. Pharmacokinetic/Pharmacodynamic Models ................................................81
6.1 Pharmacokinetic/Pharmacodynamic Analysis of Glucocorticoids .........................82
6.2 In Vivo Potency ......................................................................82
6.3 Selected Examples ....................................................................84
6.3.1 Influence of Sex on Glucocorticoid Pharmacokinetic/Pharmacodynamic Properties . . . 84
6.3.2 Influence of Age on Glucocorticoid Pharmacokinetic/Pharmacodynamic Properties 84
6.3.3 Once- Versus Twice-Daily Glucocorticoid Administration ............................84
6.3.4 Adverse Effects .................................................................85
7. Clinical Aspects of Glucocorticoid Therapy ..................................................85
7.1 Glucocorticoid Pulse Therapy ..........................................................85
7.1.1 Emergency Treatment ...........................................................86
7.1.2 Non-Emergency Treatment ......................................................86
7.2 Diseases Not Treated with Pulse Therapy ................................................87
7.3 Role of the Dosage Interval ............................................................87
7.4 Variation in Clinical Response to Glucocorticoid Therapy .................................87
8. Conclusions ..............................................................................87
Abstract
Glucocorticoids have pleiotropic effects that are used to treat diverse diseases
such as asthma, rheumatoid arthritis, systemic lupus erythematosus and acute
kidney transplant rejection. The most commonly used systemic glucocorticoids
are hydrocortisone, prednisolone, methylprednisolone and dexamethasone. These
glucocorticoids have good oral bioavailability and are eliminated mainly by
hepatic metabolism and renal excretion of the metabolites. Plasma concentrations
follow a biexponential pattern. Two-compartment models are used after intravenous
administration, but one-compartment models are sufficient after oral administration.
The effects of glucocorticoids are mediated by genomic and possibly nongenomic
mechanisms. Genomic mechanisms include activation of the cytosolic
glucocorticoid receptor that leads to activation or repression of protein synthesis,
including cytokines, chemokines, inflammatory enzymes and adhesion molecules.
Thus, inflammation and immune response mechanisms may be modified.
Nongenomic mechanisms might play an additional role in glucocorticoid pulse
therapy.
Clinical efficacy depends on glucocorticoid pharmacokinetics and pharmacodynamics.
Pharmacokinetic parameters such as the elimination half-life, and
pharmacodynamic parameters such as the concentration producing the halfmaximal
effect, determine the duration and intensity of glucocorticoid effects.
The special contribution of either of these can be distinguished with pharmacokinetic/pharmacodynamic
analysis. We performed simulations with a pharmacokinetic/pharmacodynamic
model using T helper cell counts and endogenous cortisol
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

Pharmacokinetics/Pharmacodynamics of Glucocorticoids 63
as biomarkers for the effects of methylprednisolone. These simulations suggest
that the clinical efficacy of low-dose glucocorticoid regimens might be increased
with twice-daily glucocorticoid administration.
mechanisms, pharmacodynamics, and clinical expe-
rience with systemically administered glucocorti-
coids.
Glucocorticoids have pleiotropic effects and they
are used frequently and intensively in clinical practice
for many different indications. Their anti-inflammatory
effect is used in inflammatory diseases
(e.g. asthma and rheumatoid arthritis) and their immunosuppressive
effect is used in autoimmune diseases
(e.g. systemic lupus erythematosus [SLE]) as
well as in organ transplantation (e.g. acute kidney
transplant rejection). Clinically applied dosage regimens
have been derived empirically and there is
considerable variability between patients in clinical
response to glucocorticoid treatment. The pharmacokinetics
and pharmacodynamics of glucocorticoids
have therefore been evaluated in many studies.
1. Pharmacokinetics
1.1 General
The pharmacokinetic characteristics of the vari-
ous glucocorticoids depend on their physicochemi-
cal properties. [5] Glucocorticoids are lipophilic and
are usually administered as prodrugs when given
intravenously. Preparations include the hydrophilic
phosphate and succinate esters of glucocorticoids,
which are converted within 5–30 minutes to their
active forms. [6-8] Small doses of glucocorticoids can
also be administered as an alcoholic solution. [9-11]
Generally, the indications for glucocorticoids can
be divided into two categories. The first category
includes emergency situations such as acute kidney
transplant rejection or diffuse alveolar haemorrhage
1.1.1 Absorption and Distribution
due to autoimmune diseases. In these patients, high
Glucocorticoids are well absorbed after oral addoses
of glucocorticoids are usually administered
ministration and have a bioavailability of 60–100%
intravenously. The second category includes chronic
(table I). [9,12-20] They have moderate protein binding
diseases such as rheumatoid arthritis or the nephrotand
a moderate apparent volume of distribution. The
ic syndrome. In these patients, low-dose maintenpharmacokinetics
of hydrocortisone (i.e. cortisol)
ance therapy with glucocorticoids is given orally
and prednisolone are nonlinear. Both bind to the
using the lowest active dose in order to limit severe
glycoprotein transcortin (i.e. corticosteroid binding
long-term adverse events. What is the rationale beglobulin)
and albumin. [21-23] Transcortin has a high
hind these opposing practices, how might this be
affinity and a low capacity for hydrocortisone and
explained, and how might it be improved?
prednisolone, whereas albumin has a low affinity
Pharmacokinetic/pharmacodynamic modelling but high capacity. This leads to an increase in the
allows simultaneous analysis of pharmacokinetics free glucocorticoid fraction once transcortin is satuand
pharmacodynamics [1-4] and to distinguish their
respective contribution to clinical efficacy. This
might help to improve dosage regimens for glucocorticoids,
such as intravenous pulse administration
or low-dose administration of twice-daily dose fractions.
This article aims to review and discuss the relationship
between pharmacokinetics, molecular
rated at concentrations of about 400 µg/L. Such
concentrations are achieved after administration of
hydrocortisone or prednisolone doses >20mg.
Protein binding is biologically relevant, because
only free drug can reach the biophase (i.e. the site of
action) and interact with the receptor. Therefore,
pharmacodynamic considerations have to include
protein binding. Clinically, decreased protein bind-
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)
Table I. Glucocorticoid pharmacokinetics after systemic administration. The pooled mean ± pooled standard deviation (see Appendix) and the range of the primary mean values
(minimum–maximum) are given for cases where more than one study was found [3,6,7,9-20,22,24-71]
Drug ROA Conc. F Cmax tmax t 1 /2 Vd Vd/F Vss CL CL/F PB fren ka c ke
(%) (µg/L/1mg (h) (h) (L) b (L) b (L) b (L/h) b (L/h) b (%) (%) (h –1 ) (h –1 )
dose) a
Cortisol Total 94 0.35 ± 0.08
(0.20–0.48)
Hydrocortisone d IV Total 2.0 ± 0.3 27 ± 7 32 ± 4 18 ± 4 92 ± 2
(1.7–2.1) (24–39) (92–93)
PO Total 96 ± 20 15.3 ± 2.9 1.2 ± 0.4 1.8 ± 0.5 1.4 ± 0.9 0.43 ± 0.11
Prednisolone IV Total
phosphate
Prednisolone after IV Total 88.3 ± 24.0 0.08 3.0 ± 0.4 45 ± 5 40 ± 9 9 ± 2 73 ± 4 18.0 ± 6.6 0.22 ± 0.03
prednisolone (2.3–3.8) (39–50) (19–80) (5–16) (70–76) (10.3–24.4) (0.19–0.27)
phosphate
Free 2.2 ± 0.3 141 ± 44 48 ± 15 0.27 ± 0.06
(1.7–2.7) (95–212) (20–63) (0.13–0.36)
Prednisone after IV Total 3.7 ± 1.1 3.3 ± 1.4
prednisolone (2.9–6.7) (2.1–5.3)
phosphate
Prednisolone IV Total 26 ± 13 50 ± 12 4.9 2.01 ± 0.48
succinate (44–59)
Prednisolone after IV Total 67 ± 23 12 ± 3 13.7 ± 4.2 0.19 ± 0.06
prednisolone (57–81) (11–14) (12.1–14.9) (0.19–0.20)
succinate
Prednisolone PO Total 99 ± 8 18.1 ± 5.5 1.3 ± 0.7 3.2 ± 1.0 60 ± 28 67 ± 19 13 ± 4 86 ± 6 2.0 ± 2.5 0.26 ± 0.07
(7.6–30.7) (0.9–1.6) (2.7–4.1) (30–132) (46–91) (8–23) (1.2–3.5) (0.19–0.32)
Free 4.3 ± 2.8 1.5 ± 0.7 2.5 ± 1.0 302 ± 210 81 ± 42 1.1 0.31 ± 0.10
(3.4–5.2) (1.4–1.5) (2.2–2.9) (254–350) (77–85) (0.27–0.36)
Prednisone PO Total 84 ± 13 2.4 ± 1.1 2.6 ± 1.3 3.3 ± 1.3 2.4 ± 1.0
(2.2–2.5) (2.5–2.8) (2.9–4.1) (1.6–2.0)
Prednisolone after PO Total 79 ± 14 16.6 ± 4.8 1.9 ± 1.1 3.0 ± 0.8 43 ± 12 62 ± 9 12 ± 2 10.2 ± 3.5 3.9 ± 4.2 0.29 ± 0.11
prednisone (62–99) (9.8–22.6) (1.3–3.0) (1.7–4.2) (31–48) (55–65) (7–14) (4.3–14.1) (1.3–9.7) (0.19–0.32)
Free 53 ± 10 4.2 ± 1.1 2.0 ± 0.4 170 ± 54 72 ± 15 6.0 ± 6.2
(1.6–2.6) (110–235) (38–97) (3.2–9.7)
Methylprednisolone IV Total 0.25 ± 24 ± 6 27 ± 8.2 90 ± 27 9.2
succinate 0.10 (23–25) (24.5–28.7) (82–97) (8.3–9.8)
(0.07–0.37)
Continued next page
64 Czock et al.

© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)
Table I. Contd
Drug ROA Conc. F Cmax tmax t 1 /2 Vd Vd/F Vss CL CL/F PB fren ka c ke
(%) (µg/L/1mg (h) (h) (L) b (L) b (L) b (L/h) b (L/h) b (%) (%) (h –1 ) (h –1 )
dose) a
Methylprednisolone IV Total 8.3 ± 3.3 0.8 2.4 ± 0.6 75 ± 16 90 ± 23 24 ± 7 78 ± 2 3.6 5.6 ± 3.5 0.28 ± 0.07
after (6.3–10.7) (1.7–3.2) (55–95) (57–123) (13–33) (75–82) (3.3–3.9) (3.1–9.5) (0.19–0.41)
methylprednisolone
succinate
Methylprednisolone IV Total 0.06 ± 6.1 ± 2.1 66 ± 21 1.2 ± 0.4 11.4 ± 2.5
phosphate 0.01 (5.9–6.4) (53–78) (10.1–12.7)
(0.06–0.07)
Methylprednisolone IV Total 3.0 ± 1.7 76.3 ± 71.5 ± 24 ± 8 4.9 ± 1.5 0.28 ± 0.06
after (3.0–3.1) 12.8 13.9 (23–24) (3.1–6.6) (0.23–0.33)
methylprednisolone (60.8–91.8) (55.5–87.5)
phosphate
Methylprednisolone PO Total 88 ± 23 8.2 ± 2.4 2.1 ± 0.7 2.5 ± 1.2 100 ± 45 109 ± 32 26 ± 8 1.3 1.7 ± 0.5 0.27 ± 0.08
(82–91) (4.6–10.4) (1.5–3.1) (1.6–3.4) (74–134) (96–125) (19–37) (0.23–0.31)
Methylprednisolone 79 ± 3
in vitro
Methylprednisone 75 ± 3
in vitro
Dexamethasone IV Total 3.6 ± 28 ± 7 7.7 ± 1.6
sodium phosphate 1.2
Dexamethasone IV Total 90 10.5 ± 2.8 4.6 ± 1.2 65.7 ± 81.6 ± 12 ± 4 9.9 ± 18.6 0.21 ± 0.03
after (10.2–10.8) (4.1–5.4) 17.3 16.6 (5–21) (4.0–12.4) (0.20–0.23)
dexamethasone (27.0–98) (61.2–98)
sodium phosphate
Dexamethasone PO Total 76 ± 10 8.4 ± 3.6 1.5 4.0 ± 0.9 0.16
(61–86) (1.0–2.0)
Dexamethasone 75 ± 4
in vitro
a
b
c
d
Cmax was normalised to a glucocorticoid dose of 1mg. Multiply by 10 –6 /MW to convert from µg/L to mol/L. MW of hydrocortisone = 362.5Da, prednisolone = 360.5Da,
prednisone = 358.4Da, methylprednisolone = 374.5Da and dexamethasone = 392.5Da.
Volume and clearance parameters were normalised to 70kg bodyweight.
Formation rate constant k f in the case of conversion after intravenous administration of a prodrug.
Parameter only for low doses (= 20mg) of hydrocortisone available.
CL = total clearance; CL/F = apparent clearance; C max = peak plasma concentration; Conc. = plasma concentration measured; F = fraction in % of the administered dose
systemically available; Free = unbound to plasma components; f ren = renally excreted fraction in % of unchanged drug; IV = intravenous; ka =absorption rate constant; ke =
elimination rate constant; MW = molecular weight; PB = plasma binding; PO = orally; ROA = route of administration; t max = time to reach C max; t 1 /2 = terminal half-life; Total =
plasma bound and free; Vd = volume of distribution; Vd/F = apparent volume of distribution; V ss = volume of distribution at steady state.
Pharmacokinetics/Pharmacodynamics of Glucocorticoids 65

66 Czock et al.
HSD2 capacity and even leading to saturation of the
mineralocorticoid receptor, would be expected to
have enhanced mineralocorticoid effects when ad-
ministered as two dose fractions, because the total
time when mineralocorticoid receptors are occupied
would be prolonged.
ing due to low plasma albumin concentrations correlated
with glucocorticoid adverse effects in prednisone
therapy. [72] Generally, however, alterations in
protein binding do not have much impact on drug
action. [73]
1.1.2 Metabolism and Excretion
The renal excretion of unchanged glucocorticoids
is only 1–20% (table I). [6,7,14,17,24-27] Glucocorticoid
metabolism is a two-step process. Firstly,
oxygen or hydrogen atoms are added then secondly,
conjugation takes place (glucuronidation or sulpha-
tion). Subsequently the kidney excretes the resulting
hydrophilic inactive metabolites.
Intracellular metabolism by 11β-hydroxysteroid
dehydrogenase (11β-HSD) controls the availability
of glucocorticoids for binding to the glucocorticoid
and mineralocorticoid receptors. Type 1 dehydroge-
nase (11β-HSD1) is widely distributed in glucocorticoid
target tissues and has its highest activity in the
liver. 11β-HSD1 acts mainly as a reductase, converting
the inactive cortisone to the active cortisol.
[74,75] Type 2 dehydrogenase (11β-HSD2) is
found in mineralocorticoid target tissues (kidney,
colon, salivary glands, placenta). 11β-HSD2 has a
high affinity for endogenous cortisol and by oxida-
tion, converting cortisol to cortisone, it protects the
mineralocorticoid receptor from occupation by cortisol.
[76] The activity of 11β-HSD2 varies depending
on the type of glucocorticoid, [75,76] which explains to
some extent the different mineralocorticoid activi-
ties of different glucocorticoids.
The undesired mineralocorticoid effects of glucocorticoid
treatment should be pronounced when
the capacity of 11β-HSD2 is exceeded. Therefore,
we speculate that the mineralocorticoid effects of
glucocorticoids might depend on the administration
scheme. A low glucocorticoid dose leading to concentrations
just above the protective capacity of
11β-HSD2 would be expected to have reduced
mineralocorticoid effects when administered as two
dose fractions, because both concentration peaks
would not exceed 11β-HSD2 capacity. In contrast,
higher glucocorticoid doses, exceeding the 11β-
1.2 Selected Examples
1.2.1 Cortisol, Cortisone, and Hydrocortisone
Cortisol is the active hormone produced by adrenal
synthesis and secreted after stimulation by the
pituitary hormone ACTH. Daily cortisol production
is about 10mg in healthy volunteers [77] and can
increase up to 400mg in conditions of severe
stress. [78] Endogenous cortisol concentrations show
a circadian pattern, with high concentrations in the
morning between 6:00am and 9:00am (about 160
µg/L at 8:00am in healthy volunteers) and low con-
centrations in the evening between 8:00pm and
2:00am. Cortisol is metabolised to the inactive cortisone
and further to dihydrocortisone and tetrahy-
drocortisone. Other metabolites include dihydrocor-
tisol, 5α-dihydrocortisol, tetrahydrocortisol and 5α-
tetrahydrocortisol. The biological activity of the latter
metabolites is unclear. [79,80] After suppression of
cortisol secretion by exogenous glucocorticoids,
cortisol concentrations decline rapidly. Biexponen-
tial functions are used to describe this cortisol de-
cline after prednisolone [28,29] whereas monoexponential
functions are used for the cortisol decline
after methylprednisolone. [30,31]
Hydrocortisone is chemically identical to cor-
tisol, but this name is used in order to distinguish
drug administration from endogenous production.
Hydrocortisone is well absorbed after oral adminis-
tration [9] and the disposition is biexponential. [81] The
pharmacokinetic parameters of cortisol and hydro-
cortisone are summarised in table I.
1.2.2 Prednisolone and Prednisone
Prednisolone (dehydrocortisol) is the active sub-
stance, whereas the inactive prednisone (dehydro-
cortisone) is activated by 11β-HSD1 to predniso-
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

Pharmacokinetics/Pharmacodynamics of Glucocorticoids 67
Table II. Dose-dependent pharmacokinetics of prednisolone, as shown for total concentration of prednisolone after oral administration. The
pooled mean ± pooled standard deviation (see Appendix) and the range of the primary mean values (minimum–maximum) are given for
cases where more than one study was found [19,32,35,36,53,60,67,70,71]
Drug F (%) Cmax (µg/L/ tmax (h) t 1 /2 (h) Vd/F (L) b Vss (L) b CL/F (L/h) b ka (h –1 ) ke (h –1 )
1mg dose) a
Prednisolone 20.7 ± 6.5 1.3 ± 0.8 3.0 ± 1.0 42 ± 16 54 ± 16 10 ± 3 1.8 ± 2.1 0.28 ± 0.08
(≤20mg) (16.2–30.7) (1.0–1.5) (2.7–3.7) (30–43) (46–63) (8–14) (1.4–3.5) (0.21–0.32)
Prednisolone 16.3 ± 3.5 1.3 ± 0.6 3.0 ± 0.6 64 ± 13 91 ± 24 15 ± 4 2.2 ± 2.8 0.25 ± 0.06
(25–60mg) (11.7–21.1) (0.9–1.6) (2.7–3.6) (51–74) (13–18) (1.2–3.2) (0.22–0.28)
Prednisolone 99 ± 8 11.1 ± 6.0 1.5 ± 0.5 4.0 ± 1.4 c 98 ± 54 17 ± 7 0.19 ± 0.07
(100mg) (7.6–12.3) (3.7–4.1) (87–132) (15–23)
a C max was normalised to a prednisolone dose of 1mg.
b Volume and clearance parameters were normalised to 70kg bodyweight.
c There were no significant differences between the half-lives after high and low dose prednisolone in the primary studies.
CL/F = apparent clearance; C max = peak plasma concentration; F = fraction in % of the administered dose systemically available; ka =
absorption rate constant; k e = elimination rate constant; t 1 /2 = terminal half-life; tmax = time to reach Cmax; Vd/F = apparent volume of
distribution; V ss = volume of distribution at steady state.
lone. [76] Similar to cortisone/cortisol, there is inter- meters of prednisolone and prednisone are summarised
conversion between both substances. The recycled
in table I.
proportion of prednisone has been estimated at
1.2.3 Methylprednisolone
76%. [14] Methylprednisolone (6α-methylprednisolone)
The pharmacokinetics of prednisolone and pred- has no affinity for transcortin and binds only to
nisone are complicated by dose-dependency due to albumin. [37,38] Accordingly, methylprednisolone
nonlinear protein binding. [24,32] Protein binding of pharmacokinetics are linear, with no dose-dependprednisolone
decreases nonlinearly from 95% to ency. [7,35] Methylprednisolone has many metabo-
60–70%, while the concentration increases from 200 lites, including 20-carboxymethylprednisolone and
µg/L to 800 µg/L when protein binding of prednisoterconversion
6β-hydroxy-20α-hydroxymethylprednisolone. Inlone
reaches a plateau. [18,24,33,34,82] In consequence, a
between methylprednisolone and
dose-dependent increase in the volume of distribuposition
methylprednisone has been described. [37,39] The dis-
tion (Vd) and drug clearance (CL) is observed at
of methylprednisolone is biexponential. [7,17]
doses over 20mg (table II). [19,32,35,83] However, the A two-compartment model is appropriate for intraelimination
half-life remains constant [19,32] and the venous administration of very high doses. [17] A onedose
dependencies of Vd and CL disappear when compartment model can be used with lower intrave-
free prednisolone concentrations are measured. [18,35] nous doses [30,40] and oral administration. [36] The
Prednisolone clearance decreases again only at very pharmacokinetic parameters of methylprednisolone
high doses, which can be explained by saturation of are summarised in table I.
elimination mechanisms. [27] The affinity of predni- 1.2.4 Dexamethasone
sone for transcortin is 10-fold lower than that of Dexamethasone (9α-fluoro-16α-methylpredprednisolone.
[82] Prednisolone metabolites include nisolone) has no affinity for transcortin and binds
6β-hydroxyprednisolone and 20β-hydroxypred- only to albumin. [41] The pharmacokinetics of dexanisolone.
[14,24] The disposition of prednisolone is methasone after intravenous administration are linebiexponential.
A two-compartment model is appro- ar. [11,42] A second peak after intravenous administrapriate
for intravenous administration. [27,29] One- and tion can be explained by enterohepatic recirculatwo-compartment
models can be used with oral ad- tion. [20,43] The disposition of dexamethasone is
ministration. [28,36,84] The pharmacokinetic para- biexponential [42,44] and a two-compartment model is
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

68 Czock et al.
Table III. Interactions of drugs and influence of diseases on glucocorticoid pharmacokinetics. The values are expressed as a percentage of
the value without drug coadministration or disease (which was set at 100%) from the respective study [10,12,22,26,29,30,33,39,45-52,54,55,85,88-92]
Drug Prednisolone Methylprednisolone Dexamethasone
CL/F (%) t 1 /2 (%) CL/F (%) t 1 /2 (%) CL/F (%) t 1 /2 (%)
Phenobarbital 140 80 300 45
(phenobarbitone)
Carbamazepine 180 65 440 45
Phenytoin 180 70 580 30
Rifampicin (rifampin) 140 60
Ketoconazole Unchanged Unchanged 40–50
Itraconazole Unchanged Unchanged 170 30 300
Diltiazem 83 115 67 145
Troleandomycin 190
Erythromycin
Prolonged
Clarithromycin Unchanged Unchanged 35 230
Ciclosporin Decreased Unchanged Unchanged
Sirolimus (rapamycin) 130
Grapefruit juice Unchanged 130
Disease
Renal failure 60 150 Unchanged Unchanged 165 70
Chronic liver disease Reduced Unchanged Unchanged 65 170
CL/F = apparent clearance; t 1 /2 = terminal half-life.
appropriate for intravenous dexamethasone. [43,44] prednisolone elimination. In another study, the loss
The pharmacokinetic parameters of dexamethasone of kidney transplant function was associated with
are summarised in table I. rifampicin treatment. [87]
1.3 Pharmacokinetic Drug-Drug Interactions
Coadministration of cytochrome P450 (CYP)
3A4 inhibitors (e.g. ketoconazole, clarithromycin)
decreases the clearance and increases the half-life of
1.3.1 Influence of Other Drugs on
Glucocorticoid Pharmacokinetics
methylprednisolone and dexamethasone, whereas
Coadministration of enzyme inducers (e.g. barbi- prednisolone is usually not affected (table
turates, carbamazepine, phenytoin, rifampicin [riticoids
III). [12,26,29,30,46-49] Decreased clearance of glucocor-
fampin]) increases the clearance and decreases the
can lead to increased effects (biomarker:
half-life of prednisolone and methylprednisolone lymphocytes, cortisol). [30,39,47,50,51,93-95] Clinically,
(table III). [85] A study of the time course of induction macrolides have been used as glucocorticoid-sparwith
rifampicin showed that the changes in pharmaasthma.
ing agents in patients with glucocorticoid-dependent
cokinetics of prednisolone were maximal 2 weeks
[96,97] However, short-term administration of
after the start, and were normal again 2 weeks after macrolides does not need a dose reduction of gluco-
the end of rifampicin therapy. [45] The clinical relepharmacokinetics
corticoids. Cimetidine had no influence on the
vance of such interactions was demonstrated in paprednisolone
of prednisolone [83,98] or methyl-
tients with kidney transplants treated with prednicreased
in one patient. [99] Grapefruit juice intients
sone. A lower kidney transplant survival rate was
the half-life of oral methylprednisolone [52]
found in those patients receiving concomitant anticonvulsants
but did not affect prednisolone. [88]
(phenobarbital [phenobarbitone]/ Users of oral contraceptives (OCs) have higher
diphenylhydantoin). [86] This can be explained by a concentrations [53] and a lower clearance [34] of predreduced
immunosuppressive effect due to increased nisolone, which has been explained by increased
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

Pharmacokinetics/Pharmacodynamics of Glucocorticoids 69
transcortin levels. [34] Methylprednisolone has a low- nosyltransferase induction after methylprednisolone
er clearance in OC users, [40] which has been ex- withdrawal could explain increased mycophenolate
plained by inhibition of oxidative processes by OCs. concentrations. Induction of glucuronosyltransfer-
This lower clearance of methylprednisolone, how- ase expression by glucocorticoids was demonstrated
ever, was associated with mixed changes in in vitro. [113]
glucocorticoid effects, and it was concluded that a
change in methylprednisolone dose is not necessary 1.3.3 Interactions Between Glucocorticoids and
in OC users. [40]
Ciclosporin, Tacrolimus or Sirolimus (Rapamycin)
In vitro and animal studies suggest that cortisol, The interactions between ciclosporin and glucoprednisolone,
methylprednisolone, and dexamethconflicting
corticoids are complicated and there are studies with
asone are substrates of P-glycoprotein. [100-102] Therecoids
results. Both ciclosporin and glucocorti-
fore, coadministration of P-glycoprotein inhibitors
are substrates of CYP [12,30] and possibly P-
could increase glucocorticoid absorption and might glycoprotein. [100] Ciclosporin inhibits P-glycoproteaffect
glucocorticoid distribution. Oral coadminprotein
in, whereas glucocorticoids might induce P-glyco-
istration of valspodar increased the area under the
and CYP. [106,110]
curve (AUC) of dexamethasone 1.24 times in Ciclosporin affects the pharmacokinetics of predhealthy
volunteers, although it is most likely that nisolone. The AUC of prednisolone after oral predthis
is not clinically relevant. [103]
nisone was higher, [89] and the oral clearance of pred-
Smoking did not affect the pharmacokinetics of nisolone was lower [90] in patients receiving ciprednisolone
or dexamethasone. [104]
closporin. In addition, the oral clearance of
prednisolone increased in patients who were
1.3.2 Influence of Glucocorticoids on the
switched to a ciclosporin-free regimen and de-
Pharmacokinetics of Other Drugs
creased when ciclosporin was added. [90] This might
Glucocorticoids affect the pharmacokinetics of be explained at least partially by increased absorpother
drugs by enzyme induction (e.g. of cyto- tion of prednisolone due to P-glycoprotein inhibichromes,
[105] P-glycoprotein or glucuronosyltrans- tion by ciclosporin. In contrast, another study did
ferase). Dexamethasone induced CYP3A4 at high not find changes in the pharmacokinetics of prednisdoses
(16–24 mg/day) [106] but not at low doses (1.5 olone with ciclosporin coadministration. [114] Howmg/day).
[107] Methylprednisolone at a daily dose of ever, the latter study was performed in patients only
8mg did not induce CYP3A4 in healthy volun- 1 month after transplantation and it is possible that
teers. [108] Autoinduction has been used to explain a high doses of glucocorticoids in the early posttime-dependent
increase in the prednisolone [35] and transplantation period induced P-glycoprotein and
methylprednisolone [109] clearance. P-glycoprotein CYP which counterbalanced the inhibitory effects
might be induced by lower glucocorticoid doses. of ciclosporin. Another observation is that oral pred-
Dexamethasone induced P-glycoprotein at low nisolone clearance was lower at 3–6 months than at
doses and CYP at high doses, as shown in rats. [110]

70 Czock et al.
Kidney transplant patients on ciclosporin had an mained unchanged. [10,33] The protein binding of
intravenous clearance of methylprednisolone that prednisolone decreased and thus the free fraction
was similar to the clearance in healthy volunteers increased in renal failure. [33] Methylprednisolone
from the literature. [54] Sirolimus (rapamycin) re- pharmacokinetics were unchanged in patients with
duced the oral clearance of prednisolone after pred- renal failure. Only the conversion of the prodrug
nisone and a negative correlation between sirolimus methylprednisolone succinate to methylpred-
AUC and prednisolone clearance was observed. [91] nisolone was slower. [55] In contrast, dexamethasone
Methylprednisolone affects ciclosporin pharma- clearance was increased and its half-life decreased
cokinetics. The clearance of intravenous ciclosporin in renal failure (table III). [10] This can be explained
was increased after methylprednisolone pulse ther- by decreased protein binding of dexamethasone to
apy (250 mg/day for 3 days), [116] which can be albumin in uraemia. [41] Similarly, the binding of
explained by CYP induction. In contrast, another cortisol to albumin is reduced in uraemia, [23] wherestudy
found higher ciclosporin plasma levels after as binding of cortisol to transcortin remains unmethylprednisolone
(250–500 mg/day). [117] How- changed. [22] Cortisol metabolites accumulate in reever,
in the latter study a nonspecific RIA was used nal failure and are removed insufficiently during
and thus the contribution of ciclosporin metabolites haemodialysis. [79] The fraction of prednisolone reto
the measured plasma levels is unclear. Ci- moved during a 5-hour haemodialysis was
closporin pharmacokinetics were unaffected by 7–17.5%. [121] The fraction of methylprednisolone
withdrawal of low-dose prednisolone for 24 hours in removed during haemodialysis can be estimated to
liver transplant recipients. [118] However, enzyme in- be

Pharmacokinetics/Pharmacodynamics of Glucocorticoids 71
There are a number of reports for other diseases
that may affect glucocorticoid pharmacokinetics.
Patients with the nephrotic syndrome had decreased
total but normal unbound prednisolone concentra-
tions. [123] Patients with inflammatory bowel disease
have variable absorption, [83,124] and fractional bind-
ing of prednisolone to plasma proteins was decreased
in active disease. [125] Hyperthyroid patients
had decreased prednisolone concentrations. [83] Patients
with cystic fibrosis had a higher volume of
distribution and normal half-life of oral predniso-
lone, [126] whereas prednisolone pharmacokinetics in
steroid-dependent asthmatics were unchanged compared
with healthy individuals. [127] Children with
acute lymphoblastic leukaemia had a lower clear-
ance and longer half-life. [128] Patients with acute
spinal cord injury had a lower systemic clearance of
methylprednisolone. [129]
2. Genomic and Nongenomic
Mechanisms of Glucocorticoid Effects
Glucocorticoids inhibit many events of the inflammatory
and immune response by various mechanisms
(table IV). [130,131] Most effects of glucocorticoids
are mediated by glucocorticoid receptors, but
possibly not all. Basically, glucocorticoid mechanisms
can be divided into genomic and nongenomic
mechanisms. Whereas the role of genomic mechanisms
is well established, the importance of nongenomic
mechanisms is still unclear.
2.1 Genomic Mechanisms
The genomic effects of glucocorticoids are characterised
by a slow onset and slow dissipation of
the response, due to the time-consuming process of
mRNA transcription and translation (figure 1). The
start of mRNA induction for some proteins was seen
after 15 minutes in rat thymic lymphocytes. [132] Protein
levels can be affected after 30 minutes and
effects on tissue or organ levels need hours to days.
It can be estimated that 100 to 1000 genes are up- or
down-regulated in a cell-type specific way. [133-135]
2.1.1 Glucocorticoid Receptors
The glucocorticoid receptor (GRα), a member of
a superfamily of ligand-regulated nuclear receptors,
consists of a ligand-binding domain, a DNA-binding
domain, and two activation-functional domains. The
inactive glucocorticoid receptor is retained in the
cytoplasm within a multiprotein complex containing
two heat shock protein molecules (HSP90). Addi-
tional molecules of this complex include the immunophyllins,
HSP70, p23, and src. [136-138] The gluco-
corticoid receptor isoform GRβ, a splice variant,
does not bind glucocorticoids and its relevance in
glucocorticoid resistance is controversial.
Glucocorticoids bind to the ligand-binding do-
main of the glucocorticoid receptor GRα after entering
the cell by passive diffusion through the cell
membrane. This binding leads to a conformational
change in the glucocorticoid receptor, which in turn
leads to dissociation of the multiprotein complex
(figure 1). The glucocorticoid receptor-glucocorticoid
(GR/GC) complex is then localised to the nucleus
via the nuclear pore complex. Dimerisation
with formation of glucocorticoid receptor homod-
imers is necessary for DNA interaction with gluco-
corticoid response elements (GREs) and subsequent
activation or repression of transcription (figure
1). [139,140] The transactivation potency of the GR/GC
complex is regulated intracellularly by coactivators
and corepressors, [141,142] and possibly by glucocorti-
coid receptor phosphorylation. [143,144] In addition,
monomeric glucocorticoid receptors inhibit the
proinflammatory transcription factors nuclear factor
κB (NF-κB) [figure 1] and activator protein 1 (AP-
1), independent of DNA binding. The importance of
the latter mechanism is underlined by the fact that
many inflammatory genes that are repressed by glu-
cocorticoids do not contain a negative GRE.
2.1.2 Glucocorticoid Response Elements
The GREs in gene promoters are characterised by
the nonpalindromic consensus sequence 5′-XXTA-
CAXXXTGTTCT-3′ containing two binding sites
for the glucocorticoid receptor homodimer. After
DNA association, the GR/GC homodimer (together
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

72 Czock et al.
Table IV. Molecular mechanisms of glucocorticoid effects
Mechanisms Molecular effects Cellular effects
Genomic mechanisms
Transcriptional
transactivation Interactions of GR with GREs Anti-inflammatory/immunosuppressive effects
Interactions of GR with transcription factors induction of anti-inflammatory cytokines
(→ CBP → acetylation of core histones (e.g. IL-10, TGFβ)
→ increased gene transcription)
induction of cytokine receptors
(e.g. IL-1RII, IL-10R, TGFβR)
induction of proapoptotic factors
Metabolic effects
induction of PEPCK, TAT (gluconeogenesis)
mobilisation of amino and fatty acids
Antiproliferative effects on non-immune cells
induction of p21CIP1 (e.g. renal mesangial cells)
induction of MKP-1 (e.g. osteoblasts)
Other effects
antiapoptotic effect (e.g. induction of c-IAP2)
up-regulation of β 2-receptors
transrepression Interactions of GR with nGREs Anti-inflammatory/immunosuppressive effects
Interactions of GR with transcription factors suppression of:
inhibition of AP-1, NF-κB
cytokines (e.g. IL-1, IL-2, IL-6, IL-12, IFNγ)
→ CBP associated HAT activity ↓
chemokines (e.g. MCP-1, IL-8, eotaxin)
→ inhibition of histone acetylation
receptor expression (e.g. IL-2R)
→ decreased gene transcription
adhesion molecules
direct (e.g. ICAM-1, E-selectin)
indirect via cytokine/chemokine suppression
(e.g. of IL-1β, TNFα)
inflammatory enzymes (e.g. COX-2, cPLA 2, iNOS)
T cell proliferation (e.g. via IL-2↓)
Other effects
suppression of the hypothalamic-pituitary-adrenal axis
suppression of osteocalcin
suppression of matrix metalloproteinase
Post-transcriptional Modification of mRNA stability Suppression of COX-2, MCP-1, iNOS
(shortening of the poly(A) tail)
Translational
Post-translational
Suppression of ribosomal proteins and
translation initiation factors
Protein processing, secretion
Nongenomic mechanisms
Specific
classical GR Cytosolic interactions (possibly via cPLA 2 inhibition (via src/annexin-1)
components of the GR-multiprotein complex) Tertiary CAM structure (possibly via annexin-1)
nonclassical GR Interaction with membrane GR May induce apoptosis
Interaction with other receptors
May induce IP 3, Ca2+, protein kinase C, cAMP, MAPK
Continued next page
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

Pharmacokinetics/Pharmacodynamics of Glucocorticoids 73
Table IV. Contd
Mechanisms Molecular effects Cellular effects
Nonspecific
Glucocorticoid dissolves in membranes and may
alter
→ physicochemical membrane properties
(fluidity, ‘membrane stabilisation’)
→ activity of membrane associated proteins
AP-1 = activator protein 1; CAM = cellular adhesion molecule; cAMP = cyclic adenosine monophosphate; CBP = CREB binding protein; c-
IAP2 = cellular inhibitor of apoptosis; COX-2 = cyclo-oxygenase 2; cPLA 2 = cytosolic phospholipase A 2; GR = glucocorticoid receptor; GRE
= glucocorticoid response element; HAT = histone acetylase; ICAM = intercellular adhesion molecule; IFN = interferon; IL = interleukin;
iNOS = inducible nitric oxide synthase; IP 3 = inositol-1,4,5-trisphosphate; MAPK = mitogen activated protein kinase; MCP-1 = monocyte
chemoattractant protein 1; MKP-1 = MAP kinase phosphatase 1; mRNA = messenger RNA; NF-κB = nuclear factor κB; nGRE = negative
GRE; PEPCK = phosphoenolpyruvate carboxykinase; TAT = tyrosine aminotransferase; TGFβ = transforming growth factor-β; TNF =
tumour necrosis factor.
with other cofactors) binds the transcriptional coac- proinflammatory p65-CBP HAT complex leads to
tivator CREB binding protein (CBP)/p300 which in deacetylation of specific histone residues, DNA
turn binds the basal transcription factor apparatus folding, and thus to reduced transcription or silencand
starts gene transcription. DNA transcription, ing of proinflammatory genes. [150,151] Induction of
once started, is independent of the further presence IκB or HDAC might play an additional role as a
of the GR/GC complex (‘hit and run’ princi- long-term anti-inflammatory effect of glucocortiple).
[145,146] coids. [130,152]
Acetylation and deacetylation of specific histone
residues regulates histone-chromatin interaction and 2.1.4 Post-Transcriptional and
Translational Mechanisms
thus the accessibility of genes for transcription factors.
CBP has intrinsic histone acetylase (HAT) Protein synthesis depends on the stability and
activity and thus can promote anti-inflammatory half-life of mRNA, which is regulated by the length
gene transcription via histone acetylation and concorticoids
can act by destabilising the mRNA of
of its poly(A) tail and other mechanisms. [130] Gluco-
secutive unfolding of the DNA.
proinflammatory proteins. [153,154] Additionally, glucocorticoids
might act at the translational level by
2.1.3 Transcription Factors (Nuclear Factor κB and
Activator Protein 1)
suppression of ribosomal proteins and translation
The inflammatory response of tissue cells, stimulated,
initiation factors.
for example, by tumour necrosis factor
(TNFα) or interleukin (IL)-1β, is mediated intracel- 2.2 Nongenomic Mechanisms
lularly by the proinflammatory transcription factors
NF-κB (e.g. p65-p50 heterodimer) [figure 1] and Nongenomic mechanisms are characterised by a
AP-1 (Fos-Jun heterodimer). [147,148] In later phases rapid onset of effect (

74 Czock et al.
Glucocorticoid
Cytokine receptor
Glucocorticoid receptor –
HSP90 complex
NF
IκB
−κB
Specific nongenomic
effects
NF
−κB
Anti-inflammatory genes
NF −κB GRE
Proinflammatory
genes
Fig. 1. Genomic mechanisms of glucocorticoids in human cells. Mechanisms include transactivation via binding to a glucocorticoid response
element (GRE) in the promoter region of a gene (e.g. interleukin-10 gene) and transrepression via inhibition of the transcription factor NFκB.
HSP90 = heat shock protein 90; IκB = inhibitor of NF-κB; NF = nuclear factor.
Nongenomic effects have been used to explain
the increased clinical effect of pulse therapy with
glucocorticoid doses >250mg. Genomic mechanisms
are not sufficient to explain such effects, as it
has been estimated that all glucocorticoid receptors
are occupied after prednisolone 100–200mg. [157] Ef-
fects associated with nongenomic mechanisms can
lead to different in vitro drug potencies compared
with genomically mediated effects. [160,161]
2.2.1 Specific Nongenomic Mechanisms
Specific nongenomic mechanisms are mediated
via the classical glucocorticoid receptor (figure 1) or
nonclassical glucocorticoid receptors. [159] For exam-
ple, a fast (

Pharmacokinetics/Pharmacodynamics of Glucocorticoids 75
liberation of annexin 1 (formerly called lipocortin lysosomal membranes might be another mechanism
1), which interferes with intracellular signal trans- (figure 2). [165]
duction and eventually inhibits cPLA activation. [136]
Experiments with cells from an annexin 1 knockout 3. The Host Defence Response and the
mouse support these findings. [162]
Effects of Glucocorticoids
2.2.2 Nonspecific Nongenomic Mechanisms
In order to understand the multiple effects of
Nonspecific nongenomic mechanisms are due to
glucocorticoids, a review of the host defence resdirect
interaction of glucocorticoids with cell meminflammation,
the immune response, coagulation,
ponse is needed. The host defence response includes
branes. It has been suggested that the lipophilic
steroids physically dissolve into lipid membranes
tissue repair and activation of the hypothalamic-
and modify physicochemical membrane properties,
pituitary-adrenal axis.
which in turn affect the activity of membrane-associated
proteins. [163,164] Suppression of cellular energy
3.1 Molecular Mechanisms
metabolism leading to reduced cell function On the molecular level, inflammation and the
could be a consequence. [157] Stabilisation of immune response are mediated by cytokines (e.g.
Glucocorticoid
?
Basement
membrane
?
Cell membrane
Lysosome
Fig. 2. Nonspecific nongenomic mechanisms of glucocorticoids. These might affect membranes by physicochemical mechanisms. Involved
membranes include cell membranes, lysosomal membranes and possibly basement membranes.
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

76 Czock et al.
IL-1 to IL-6, IL-11 to IL-13, TNFα, interferon iNOS, which generates nitric oxide, is involved
[IFN]γ, macrophage migration inhibitory factor in vasodilatation at the site of inflammation. Gluco-
[MIF]), chemokines (e.g. IL-8, monocyte chemoat- corticoids can suppress iNOS expression by trantractant
protein [MCP]-1, macrophage inflamma- scriptional and post-transcriptional mechanisms as
tory protein [MIP]1α, regulated upon activation nor- shown in vitro. [169,170] Glucocorticoid treatment remal
T cell expressed and secreted [RANTES], duced nitric oxide levels in exhaled air in patients
eotaxin), kinins and kinin receptors, adhesion mole- with pulmonary sarcoidosis or cystic fibrosis. [171,172]
cules, and inflammatory enzymes (e.g. inducible
nitric oxide synthase [iNOS], cyclo-oxygenase
[COX]-2).
3.2 Cellular Mechanisms
3.1.1 Cytokines and Chemokines
3.2.1 Cell Trafficking and Adhesion Molecules
Cytokines, extracellular signalling proteins that The inflammatory process depends on migration
induce cellular responses, affect protein production, of inflammatory and anti-inflammatory immune
antigen expression and proliferation. Glucocorti- cells to the site of inflammation (cell trafficking).
coids act by suppression of proinflammatory cytochemokines
Activation of immune cells is mediated by
kines (e.g. IL-1β, IFNα), induction of decoy recepcells
(e.g. MCP-1, IL-8). Exit of immune
tors that trap proinflammatory cytokines (e.g.
from the blood vessels is mediated by cellular
IL-1RII), induction of anti-inflammatory cytokines adhesion molecules (CAMs). [173]
(e.g. transforming growth factor [TGF]-β, IL-10), Glucocorticoids can reduce the recruitment of
and induction of anti-inflammatory cytokine recepsion
immune cells to the site of inflammation by repres-
tors (e.g. TGFβR, IL-10R). [135,166]
of adhesion molecules, either directly as shown
Chemokines, extracellular signalling proteins in vitro [174,175] or indirectly via suppression of prointhat
affect cellular migration, can be suppressed flammatory cytokines and transcription factors. In
(e.g. MCP-1 = CCL2, IL-8 = CXCL8, MIP-1β = addition, glucocorticoids can induce rapid changes
CCL4, eotaxin = CCL11) or induced (e.g. internongenomic
in the surface distribution of CAMs, possibly by a
feron-inducible protein IP-10 = CXCL10,
mechanism. [173,176] Glucocorticoid-in-
fractalkine = CX3CL1) by glucocorticoids. duced granulocytosis can be explained by limited
neutrophil emigration from the blood and neutrophil
3.1.2 Inflammatory Enzymes mobilisation from the bone marrow.
Arachidonic acid, an important mediator of the
inflammatory response, is produced by phospho- 3.2.2 T Cell Differentiation
lipase A2 (PLA2). Arachidonic acid is metabolised T Cell subsets include CD4+ helper (Th) cells,
by COX, by thromboxane synthase, and by lipox- CD8+ cytotoxic T (Tc) cells, CD4+CD25+ natural
ygenase, but arachidonic acid may also have direct regulatory T (Tr) cells and adaptive/inducible regueffects
itself as a second messenger. [167] COX-2, the latory T (Treg1) cells [177,178] and CD8+CD28- supinducible
COX, is induced by inflammatory and pressor T cells. [179] Naive T helper (Th0) cells differmitogenic
stimuli.
entiate to Th1 or Th2 cells depending on the stimu-
Glucocorticoids suppress cytosolic cPLA2 and lus. [180] Regulatory T cells suppress immune
COX-2 expression via genomic mechanisms. [168] responsiveness and induce tolerance. [181] Natural Tr
Additionally, a specific nongenomic mechanism has cells express membrane-bound TGFβ that can delivbeen
suggested for suppression of cPLA 2 ac- er signals to target cells via a contact-dependent
tivity. [136] As a consequence, the production of process. [182] Adaptive Treg1 cells produce IL-10 and
arachidonic acid and its metabolites is decreased. TGFβ. [178]
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

Pharmacokinetics/Pharmacodynamics of Glucocorticoids 77
Glucocorticoids inhibit the costimulatory CD40- philic inflammation prevails. In contrast, glucocortiligand
on lymphocytes [135] and costimulatory mole- coids decrease the rate of apoptosis in neutrophilic
cules on dendritic cells (e.g. CD40, CD86). [183] granulocytes, which could explain the limited clin-
Eventually, dendritic cells are switched to produce ical efficacy of long-term glucocorticoid treatment
IL-10 instead of IL-12, [184] which in turn limits in chronic obstructive pulmonary disease, where
differentiation of Th0 to Th1 cells. In addition, neutrophilic inflammation prevails. [193,194]
glucocorticoids might induce differentiation of Th0 Glucocorticoids can induce apoptosis by several
to Treg1 cells. [185,186] Up-regulation of TGFβ recep- mechanisms. Firstly, cytokines that represent survitors
on lymphocytes might enhance the action of val factors for immune cells are down-regulated by
regulatory T cells.
glucocorticoids, which can lead indirectly to
apoptosis. Secondly, glucocorticoids might induce
3.2.3 Cell Proliferation proapoptotic factors. Thirdly, glucocorticoids might
Glucocorticoids affect the proliferation of inhibit NF-κB mediated antiapoptotic mechanimmune
and nonimmune cells. Indirect glucocorti- isms. [195]
coid effects include inhibition of T cell growth fac- Antiapoptotic mechanisms of glucocorticoids intor
production (e.g. IL-2), which leads to reduced T clude induction of receptors for antiapoptotic sigcell
proliferation. Direct glucocorticoid effects in- nals [196] and induction of intracellular antiapoptotic
clude transcription of the protein p21CIP1, an inhibi- factors (e.g. the cellular inhibitor of apoptosis c-
tor of cyclin-dependent kinase, which leads to cell IAP2). [197]
cycle arrest as shown in renal mesangial cells. [187]
Importantly, glucocorticoids have to be studied over 3.2.5 Basement Membranes
a wide concentration range. Low to medium concentein-free
The renal glomerulus normally produces a pro-
trations of prednisolone (10 –9 to 10 –6 mol/L) stimupermeability
filtrate, but in the nephrotic syndrome the
lated intestinal epithelial cell proliferation, whereas
of the glomerular capillary wall for
very high concentrations (10 –4 mol/L) inhibited increase
macromolecules is increased. Glucocorticoids detestinal
epithelial cell proliferation. [188]
proteoglycan synthesis in glomerular epi-
thelial and mesangial cells by genomic mechan-
3.2.4 Apoptosis isms. [198,199] Glucocorticoids inhibit the release of
Glucocorticoids have apoptotic or antiapoptotic matrix metalloproteinases, as shown in alveolar
effects, depending on the cell type. Apoptosis of macrophages. [200] In addition, nonspecific glucocorimmune
cells (e.g. lymphocytes) leads to attenua- ticoid effects on basement membranes might be
tion of the inflammatory and immune response, assumed.
whereas antiapoptotic effects could protect resident
cells (e.g. epithelial cells) of the inflamed tissue. [189]
3.3 Inflammation
Apoptosis of T cells could be an important mechanism
of intravenous glucocorticoid pulse therapy. Acute inflammation is characterised by four con-
Administration of methylprednisolone 500–1000mg secutive phases. These are exudation, local infiltrainduced
apoptosis of T helper cells in patients with tion by neutrophils, apoptosis of neutrophils, and
autoimmune diseases. [190,191] The degree of T cell local infiltration of mononuclear cells. Exudation is
apoptosis was dependent on the glucocorticoid dose due to increased vascular permeability of capillaries
in an animal model. [192]
and venules. Vasoactive factors (e.g. nitric oxide,
Glucocorticoids increase the rate of apoptosis in prostacyclin) and reduced adrenergic receptor aceosinophilic
granulocytes in vitro, which could be tivity lead to dilatation of arterioles producing local
important in the treatment of asthma, where eosino- erythema and heat. Infiltration by neutrophils is
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

78 Czock et al.
mediated by adhesion molecules and chemokines. regulated in acute rejection [205,209] could play a role.
Apoptosis and phagocytosis of neutrophils by Finally, inhibition of the effector mechanisms of
mononuclear cells is important for the resolution of transplant destruction might be involved in glucoinflammation,
which is coordinated by anti-inflam- corticoid efficacy.
matory mediators derived from arachidonic acid
(e.g. lipoxins and cyclopentane prostaglandins
[cyPGs]) and by anti-inflammatory cytokines (e.g.
4. Adverse Effects of Glucocorticoids
IL-10, TGFβ). [149]
It is a general observation that adverse effects of
Glucocorticoids counteract the acute inflammaglucocorticoid
treatment appear more likely after
tory effects on the microcirculation resulting in
long-term treatment but less frequently after shortvasoconstriction,
reduction of oedema and a determ
treatment, even with high glucocorticoid
creased rate of leucocyte migration. [201] In addition,
doses. [210] This observation is compatible with timeglucocorticoids
could affect the resolution of independent
genomic effects that do not increase furflammation
by inducing annexin-1 derived peptides
ther after high doses when glucocorticoid receptor
that act at the lipoxin A4 receptor. [202] Glucocortisaturation
is already achieved.
coid treatment increases IL-10, [203] which inhibits
NF-κB activity and affects many immune cells. [204] Glucocorticoids induce or aggravate diabetes
mellitus and induce arterial hypertension. [211-213]
3.4 Immune Response
Glucocorticoids negatively regulate the hypothalamic-pituitary-adrenal
(HPA) axis and rapidly inhibit
The following events are involved in the immune adrenal secretion of cortisol. Long-term inhibition
response: (i) antigen processing/presentation and acnal
can lead to adrenal atrophy. [214] Unfortunately adre-
tivation of macrophages/dendritic cells; (ii) antigen
suppression cannot be predicted from the dose or
recognition and activation of T cells; (iii) generation duration of glucocorticoid therapy. [215] One of the
of T helper cell response; (iv) production of proinapy
most serious adverse effects of glucocorticoid ther-
flammatory cytokines; (v) adhesion and migration;
is the increased risk of infection. [216,217] The risk
(vi) inflammation and cell injury; and (vii) repair increases with the dose and duration of glucocortiand
restitution. All of these events can be affected coid treatment.
by glucocorticoids.
Long-term treatment with glucocorticoids causes
In acute kidney transplant rejection T helper cells osteoporosis by various mechanisms affecting osreact
in a Th1 type immune response [205] after recogcally,
teoblastic and osteoclastic functions. [211,218,219] Clininition
of donor antigen. [206] Glucocorticoids act on
the fracture risk increases with the glucocorti-
various levels of transplant rejection. They inhibit coid dose [220] and correlates better with the daily
the differentiation and antigen presentation of dose compared with the cumulative dose. [221] Skin
macrophages and dendritic cells [184,207] and thus supferation
atrophy is due to suppression of cutaneous cell proli-
press the initiation of an immune response. Glucoglucocorticoids.
and protein synthesis (e.g. collagen) by
corticoids inhibit proinflammatory cytokine produccorticoid
Skin thinning begins after glucocorticoids
tion of IL-1, IL-2, IL-6, IL-12, IFNγ and TNFα in
treatment for only a few days. [211]
various cells, [208] leading to suppression of activated Other adverse effects associated with glucocorti-
T cells. In addition, apoptosis of T cells is induced coid therapy include gastrointestinal ulcers (controby
glucocorticoid pulse therapy, [190,191] which could versial), [211,222,223] cataract formation, [224] redistribualso
be important in the treatment of acute transplant tion of body fat, dyslipidaemia, myopathy, bone
rejection. Furthermore, down-regulation of adhesion necrosis, [225] growth retardation in children, [226]
molecules and chemokine receptors that are up- glaucoma, psychosis, increased appetite and, rarely,
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

Pharmacokinetics/Pharmacodynamics of Glucocorticoids 79
allergic reactions. [227] Increased appetite can also be At the tissue/organ level, topical skin blanching
a desired effect, e.g. in cancer patients. [228] as a result of vasoconstriction of the skin microvasculature
has been used as a biomarker for dermato-
5. Pharmacodynamics logical glucocorticoid products. [241,242]
of Glucocorticoids
The pharmacodynamic properties of a drug are
5.2 Potency
the mathematical description for the quantitative The effect (E), as measured by a change of a
relationships between drug concentration and ef- biomarker, depends on drug concentration (C). The
fects.
basic correlation between effect and concentration is
described by the sigmoid Emax model, where Emax is
5.1 Biomarker and Surrogate Endpoints the maximum achievable effect (capacity parameter)
and CE50 is the concentration producing the
Many studies have analysed the pharmacohalf-maximal
effect (sensitivity parameter). The latdynamics
of glucocorticoids, but the results vary
depending on the biomarker used. There are many
ter has also been named EC50, CI50, or IC50, depen-
biomarkers, but only a few well-evaluated surrogate
ding on circumstances. The sigmoidicity constant H
endpoints (e.g. HbA1c for complications of diabetes
determines the slope of the curve (equation 1).
H
mellitus, bone mineral density for fracture risk in
C
E = E ·
max H H
osteoporosis).
CE
50
+ C
At the molecular level, endogenous cortisol is
(Eq. 1)
used as a biomarker for HPA suppression. [30] Osteo-
The parameter CE50 is a hybrid of receptor affinicalcin,
secreted by osteoblastic cells during ostety,
the number of receptors, and subsequent effector
ogenesis, is used as a biomarker for glucocorticoid
mechanisms. The potency of a drug is calculated as
effects on bone formation. [57,229] Molecular markers
the inverse of CE50, since a high potency indicates
used in vitro to evaluate glucocorticoid potencies
that only a low concentration is needed to produce
include transcription factors (e.g. AP-1, NF-κB),
the half-maximal effect (equation 2).
mRNA levels and gene expression (e.g. cytokines or
membrane proteins). [230-234] 1
Potency =
At the cellular level, the number of T cells is a
CE
50
frequently used biomarker in vivo because T cells
(Eq. 2)
play a central role in the immune response. [30,31,58-60] The relationship between drug concentrations
The suppression of CD4+ (T helper) cells by gluco- and effects can be determined in vitro where concorticoids
might be a surrogate endpoint for the stant concentrations and a defined exposure time are
prevention and treatment of transplant rejection and used. Eventually an in vitro CE50 is calculated. In
the therapy of autoimmune diseases. On the other vivo, drug concentrations are constantly changing
hand, low CD4 counts in long-term immunosup- and the different half-lives of glucocorticoids influpression
were correlated with an increased frequen- ence the duration of effect and obscure drug potency
of infections, [235] neoplasms [236,237] and athero- cy. [243] The influence of both factors (CE 50 and drug
sclerosis. [238] The number of circulating blood cells half-life) on the effect can be distinguished by pharreflects
migration between the intravascular and ex- macokinetic/pharmacodynamic analysis and an estitravascular
compartments, [31] but apoptosis might mation of in vivo CE50. Importantly, when in vitro
play an additional role after very high glucocorticoid and in vivo CE 50 s are compared, protein binding has
doses. [190,191] Lymphocyte activation and prolifera- to be considered. Such a comparison is further comtion
are used as a biomarker in vitro. [61,239,240] plicated because local (biophase) concentrations
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

80 Czock et al.
have to be used depending on the selected biomarker.
These local concentrations are determined by
drug distribution and local glucocorticoid metabolism.
contrast, using COX-2 expression as a biomarker,
hydrocortisone had a lower CE50 (7.5 × 10 –8 mol/L)
compared with dexamethasone (1 × 10 –7 mol/L).
Furthermore, prednisolone inhibited COX-2 expression
and not cPLA2 activity, but methylprednisolone
inhibited cPLA2 activity and not COX-2 expres-
sion. [160] These results can be explained only by
distinct cellular pathways (i.e. nongenomic mechanisms
in the case of cPLA2 inhibition). Another study
analysed COX-2 expression and activity in human
monocytes and found a low CE50 for dexameth-
asone, a medium CE50 for methylprednisolone, and
a high CE 50 for hydrocortisone, in agreement with
receptor binding affinities. [232] These contradictory
results could be due to the cell type studied (immune
cell vs lung cell), but can also be explained by the
design of the experiments. Croxtall et al. [160] used an
incubation period of 3 hours, whereas Santini and
colleagues [232] used a 24-hour period. The short in-
cubation period of 3 hours is thought to favour
nongenomic effects, whereas an incubation period
of 24 hours would favour genomic effects.
Nongenomic effects of glucocorticoids on cellular
energy mechanisms have been suggested. [157]
Cellular oxygen consumption is a biomarker for
leucocyte activation, as immune functions require
energy. Oxygen consumption by peripheral blood
mononuclear cells was increased in patients with
rheumatic disease and normalised after glucocorti-
coid treatment. [248] Using cellular energy consump-
tion as a biomarker, the following relationship was
found in vitro: dexamethasone (1.2) > methylprednisolone
(1.0) > prednisolone (0.4) [relative
drug potencies compared with methylpred-
The potency of a given glucocorticoid differs
depending on biomarker and cell type, despite the
glucocorticoid receptor being the same in different
cells and tissues. Potency differences between bi-
omarkers are explained by diverse effector mechan-
isms. Potency differences between cell types might
be explained by a different number of glucocorticoid
receptors per cell, by a different glucocorticoid
binding affinity due to the phosphorylation status of
the glucocorticoid receptor, [143,144] possibly by glu-
cocorticoid receptor diversity, [244] by intracellular
modulation of the transactivation potency of the GR/
GC complex by coactivators and corepressors, by a
different histone deacetylase activity, [245] and possibly
also by differences in nongenomic mechanisms
between cell types.
The potency for a given effect differs between the
various glucocorticoids. This potency has been correlated
with glucocorticoid affinity for the glucocor-
ticoid receptor. [3,36,234,246] For example, there was a
good correlation between the relative glucocorticoid
receptor affinity of various glucocorticoids and the
inhibition of whole-blood lymphocyte prolifera-
tion. [247] How different glucocorticoid receptor affinities
translate to different effects is not entirely
clear. There is evidence that the molecular structure
of different glucocorticoids does not influence the
DNA binding affinity of the glucocorticoid receptor,
but has allosteric effects on glucocorticoid receptor-
DNA dissociation. [146] nisolone]. [161]
The ranking of glucocorticoid potencies depends
on the experimental design. Experiments looking at
5.3 Clinical Efficacy
genomic effects can lead to other rankings of
glucocorticoid potency compared with nongenomic Clinical efficacy depends on pharmacodynamic
effects. For example, using cPLA2 activation as a (e.g. potency) and pharmacokinetic (e.g. duration of
biomarker, dexamethasone had a lower CE50 (2 × the drug at the receptor site) characteristics of a
10–8 mol/L), and thus higher potency compared with drug. Taken together, both parameters determine the
hydrocortisone (CE50 7.5 × 10 –8 mol/L) in A549 duration of the momentary effect, which in turn
cells (a human lung adenocarcinoma cell line). In correlates with overall clinical efficacy:
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

Pharmacokinetics/Pharmacodynamics of Glucocorticoids 81
potency + presence at the receptor site
→ momentary effect course (effect duration)
sum of momentary effects → clinical efficacy
Mathematically, pharmacokinetic/pharmacodynamic
models describe the momentary effect course.
This effect course is characterised by the duration of
effect (i.e. the time until the effect drops below a
specified value). The momentary effect course can
be summed up as the area under the effect-time
curve (AUETC or AUEC) or as the area between the
baseline and effect curve (ABEC), which are assumed
to correlate with the clinical effect. [249]
5.4 Pharmacodynamic
Drug-Drug Interactions
Drug-drug interactions can occur on a pharmacodynamic
level when the same effector pathways
are involved. For example, synergistic effects
of prednisolone, ciclosporin and sirolimus on lymphocyte
proliferation have been demonstrated in
vitro. [250] Recombinant human IL-10 and prednisolone
additively inhibit lymphocyte proliferation in
vitro. [239] In vivo, IL-10 increases prednisolone-induced
lymphocyte suppression and neutrophil stimulation,
but decreases prednisolone-induced monocyte
suppression. These changes were due to altered
glucocorticoid potency whereas pharmacokinetics
were unchanged. [62]
Theophylline has a glucocorticoid-sparing effect
in patients with asthma, [251] which can be explained
on a molecular level by enhanced HDAC activity in
epithelial cells and macrophages. [252] In contrast to
theophylline, smoking reduces HDAC activity,
which might explain the enhanced expression of
inflammatory mediators in smokers. [253] Clarithromycin
increases the glucocorticoid sensitivity of
lymphocytes from patients with asthma as measured
by suppression of lymphocyte activation in vitro. [254]
Glucocorticoids and β 2 -agonists act synergistically
on bronchial smooth muscle cell proliferation as
shown in vitro. [255]
6. Pharmacokinetic/
Pharmacodynamic Models
Generally, mathematical models can be put into
two categories: (i) models of data, also called empirical
or descriptive models; and (ii) models of sys-
tem, also called mechanistic or explanatory models.
[256,257] For predictions, usually a mechanistic
model and a critical evaluation of the model is
required. Predictions can include the pharmacody-
namic response to altered dosage regimens (i.e.
dose, timing, route of administration), [63,258,259] the
pharmacodynamic response to altered pharmaco-
kinetics (e.g. elimination conditions), or prediction
of clinical pharmacodynamics based on in vitro
data. [3,5]
The pharmacokinetic part of the pharmacokinetic/pharmacodynamic
model depends on the pharmacokinetics
of the administered drug. Free drug
concentrations should be measured if the pharmaco-
kinetics of total drug concentrations are nonlinear or
if inclusion of constants from in vitro measurements
in the pharmacodynamic model is desired. The phar-
macodynamic part of the pharmacokinetic/pharma-
codynamic model depends on the selected bi-
omarker. In the case of receptor-mediated effects,
the Emax and the sigmoid Emax models are the most
widely used. [4] Generally, the simplest model, which
explains observations satisfactorily and makes cor-
rect predictions of future experiments, is regarded as
an appropriate model. Therefore the sigmoid Emax
model (using three model parameters) should only
be chosen if the simple Emax model (using two
model parameters) is not sufficient. Pharmacokine-
tic/pharmacodynamic models including clinical
endpoints (e.g. transplant rejection, response rate,
disease progression [260] ) have not been published yet
for glucocorticoids.
A lag between the time of maximum effect and
the time of maximum concentration may be ex-
plained by the link in the pharmacokinetic and pharmacodynamic
model. Firstly, a hypothetical effect
compartment can be presumed (biophase distribu-
tion model). [1,4] However, it has been argued that
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

82 Czock et al.
this approach is only valid if the lag time is due to pools by physiological mechanisms needs some
protracted drug delivery to the biophase. Secondly, time, and the effect delay is thus explained by a
an indirect response model should be used if the physiological mechanism. [30,31,58,61,84] A comparison
mechanism is, for example, inhibition of the produc- between an indirect response model (formerly
tion of a biomarker, such that the observed decrease named direct suppression model) and an effect comin
this biomarker depends on time-limited elimina- partment model (using the Emax model, the sigmoid
tion through other mechanisms. [1,261] Both models E max model or a threshold E max model) for gluco-
(effect compartment vs indirect response model) can corticoid effects (biomarker: basophil count) remimic
each other under certain circumstances, [262] vealed that the indirect response model provided
but model selection based on mechanistic know- more consistent results. [6]
ledge of the drug action should provide a more Inclusion of a baseline function into the model is
reliable model. [263] Thirdly, a transduction model necessary for biomarkers that display a circadian
should be used if time-dependent transduction pro- pattern (e.g. endogenous cortisol, blood lymphocesses
are involved. [1,61,264] A fourth option is to cytes, osteocalcin [265] ). A number of methods to
include a lag time. [3,64,65] The latter option lacks a account for baseline variation of endogenous corphysiological
basis, but satisfactory predictions tisol have been compared recently and the method
have also been possible with such a model. [3,65] using Fourier analysis proved to be the best. [266]
Simpler and more often used methods are the use of
6.1 Pharmacokinetic/Pharmacodynamic sinus functions [24,30,61] and the use of a linear release
Analysis of Glucocorticoids
model. [267,268] When baseline variation is disregarded,
the effect might be overestimated and the con-
Effect compartment models have been used for centration CE50 would be lower compared with a
the description of lymphocyte suppression by model where a baseline function is included (e.g.
glucocorticoids, which is maximal 4–6 hours after CE 50 = 1.5 µg/L [64] vs 20.12 µg/L [68] for T helper
the maximum glucocorticoid concentration is cell suppression by methylprednisolone). Advanced
reached. [60,66,67] However, it is unlikely that drug models can also explain the circadian pattern of
distribution to the biophase is the physiological lymphocytes by the circadian pattern of cortisol
mechanism that explains the delay of the glucocorti- secretion. [31,59]
coid effect on lymphocytes. Therefore, using lym- Sophisticated mechanistic models including mophocyte
suppression as a biomarker, the effect com- lecular aspects like glucocorticoid receptor downpartment
model would be classified as a descriptive regulation have been developed and evaluated in
model. Notably, the estimated CE 50 values varied animal models. [133,269]
depending on the applied dose level, [60,67] which
indicates selection of the wrong model because
CE50, as a parameter of the drug, should be independent
6.2 In Vivo Potency
of the dosage scheme. However, another expla- We have summarised the in vivo CE50 values of
nation could be the measurement of total and not selected glucocorticoids in table V. In order to comfree
plasma concentrations of prednisolone in these pare different glucocorticoids, a potency ratio can be
studies.
calculated from their CE 50 values for a given bi-
Indirect response models have been used for omarker. For example, a potency ratio of 17.1 was
glucocorticoid effects on blood cell count and en- found for T helper cell suppression by methyldogenous
cortisol. In these models, cell migration or prednisolone compared with cortisol. [31] Comparing
secretion of cortisol into the blood is blocked by the CE50 values for various biomarkers of estimated
glucocorticoids. Elimination of pre-existing blood free methylprednisolone and free prednisolone
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)
Table V. Glucocorticoid pharmacodynamics. The concentrations producing the half-maximum effect CE50 (µg/L) of selected glucocorticoid effects are shown. The pooled mean ±
pooled standard deviation (see Appendix) and the range of the primary mean values (minimum–maximum) are given for cases where more than one study was
found [3,6,24,25,28-31,36,40,43,55,57-59,61-68]
Drug Drug plasma Cellular effects Adverse effects
concentration lymphocyte T helper cell cytotoxic T basophil monocyte neutrophil cortisol glucose osteocalcin water
measured suppression suppression cell a suppression suppression induction suppression induction suppression retention
suppression
Cortisol/ Total 6.7 ± 4.9 b 67.9 ± 20.7 103.0 ± 17.5 179.0 ± 66.2 4.6 ± 5.3
hydrocortisone (56.4–79.3)
Free 15.4 ± 3.4
Prednisolone Total 125.3 ± 65.2 61.9 ± 40.6 9.7 ± 3.4
(90.4–173.9) (48.8–75.0) (9.0–10.3)
Free 9.7 ± 7.8 5.8 ± 6.7 12.1 ± 8.1 5.7 ± 6.4 10.5 ± 6.1 29.2 ± 31.5 0.9 ± 1.3 4.5
(4.7–15.1) (3.2–15.1) (4.8–19.2) (15.0–57.7) (0.3–1.9)
Methylprednisolone Total c 10.5 ± 11.8 ± 11.5 d 51.0 ± 43.3 7.2 ± 6.1 22.4 ± 27.5 1.0 ± 1.1 102.7 8.8
13.9 (1.4–22.8) (18.5–112.0) (2.1–14.3) (8.4–36.0) (0.1–2.9)
(6.0–13.9)
Dexamethasone Total c 2.9 ± 1.0 4.0 ± 4.7 18.0 ± 4.7 3.7 ± 5.3 0.1 ± 0.07 26.9
a
(0.9–6.0) (2.2–6.1)
These CD3+/CD8+ cells were named T suppressor cells in other studies.
b This very low value is most probably due to the lack of a baseline function in the original model. [66]
c
When free concentrations were given, these were converted to total concentrations using the free fraction given in the respective study.
d One study used the sigmoid Emax model and estimated the sigmoidicity parameter H as 1.2 ± 0.1. [64]
Emax = maximal effect; Free = unbound to plasma components; Total = plasma bound and free.
Pharmacokinetics/Pharmacodynamics of Glucocorticoids 83

84 Czock et al.
(table V), we find potency ratios between 1 and 6. In 6.3.3 Once- Versus Twice-Daily
Glucocorticoid Administration
accordance with these ratios, a retrospective study
of kidney transplant patients suggested that methylolone
and methylprednisolone concentrations fall to
Due to their short elimination half-lives, prednis-
prednisolone might be superior to prednisolone for
below their CE50 values (biomarker: T helper cells)
maintenance immunosuppression. [270]
within 12 hours after administration (low dose).
Eventually the number of T helper cells increases
6.3 Selected Examples again and also shows a small rebound. This rebound
can be explained by ongoing suppression of endogenous
cortisol (the CE50 for cortisol suppression is
6.3.1 Influence of Sex on Glucocorticoid
lower than the CE50 for T helper cell suppression),
Pharmacokinetic/Pharmacodynamic Properties
which in turn leads to further diminished T helper
Pharmacokinetic differences between males and
cell suppression.
females have been reported for prednisolone and
As T helper cells play a central role in transplant
methylprednisolone. The prednisolone clearance is
rejection, it has been suggested that the efficacy of
lower [84] but methylprednisolone clearance is glucocorticoids might be increased by twice-daily
higher [68] in females compared with males. How- compared with the traditional once-daily adminisever,
based on pharmacodynamic measurements, it tration. [64,67] Thus, glucocorticoid efficacy would be
was concluded that dose adjustment is not neces- greater, which might allow a lower total daily
sary. [68,84] For example, the higher clearance of dose. [63] Theoretically, adverse effects with CE50
methylprednisolone in women was compensated by values higher or equal compared to the peak concentration
a higher potency (i.e. a lower CE 50 ), leading to the
should be reduced in parallel with the total
same overall effect. [68] The conclusions from these daily dose.
studies are limited to the biomarkers employed, but In order to compare once-daily with twice-daily
they underline the importance of performing pharmethylprednisolone
administration we performed a simulation with
macodynamic analyses.
8mg once-daily versus 4mg
twice-daily. We used an established model and published
6.3.2 Influence of Age on Glucocorticoid
parameter values for methylprednisolone ef-
Pharmacokinetic/Pharmacodynamic Properties fects on T helper cells and endogenous corti-
The frequency and severity of adverse events
sol. [30,273] The pharmacokinetic part of the model
may be increased in elderly patients. Baseline cornamic
part was a precursor-dependent indirect res-
was a one-compartment model and the pharmacodytisol
is similar in young and elderly males, but
ponse model (see Appendix). Simulations were
adrenal suppression (biomarker: endogenous cordone
with the use of the software WinNonlin Profestisol)
after administration of methylprednisolone
sional 4.0.1 (Pharsight Corporation, California).
was greater in the elderly. [271] This can be explained
The total effect correlates with the area between the
by a decrease in methylprednisolone clearance to
baseline curve without drug administration and the
66% and an increase in the half-life to 130% in the effect curve after drug administration. This simulaelderly
(69–82 years) males. [69] Also prednisolone tion showed that twice-daily administration has a
clearance was lower (62%) in elderly subjects greater total effect despite the same total dose (fig-
(65–89 years). [272] However, in the latter study adre- ure 3). The total effect of methylprednisolone on T
nal suppression (biomarker: endogenous cortisol) helper cells is stronger and the rebound of T helper
after administration of prednisolone was lower in cells is lower after twice daily administration. Thus,
the elderly.
a lower total dose might be possible. However,
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

Pharmacokinetics/Pharmacodynamics of Glucocorticoids 85
T helper cells (cells/µL)
1250
1000
750
500
250
T helper cells without methyprednisolone
administration (baseline curve)
Methylprednisolone 8mg once daily
Methylprednisolone 4mg twice daily
0
0
8:00 16:00 0:00 8:00
200
150
100
Time (h)
Fig. 3. Effect of methylprednisolone on T helper cells after 8mg
once or 4mg twice daily administration. Methylprednisolone concentrations
(lower two curves) and effect on T helper cell counts
(upper three curves) after methylprednisolone were simulated using
an established model and published parameter values (see Appendix).
[30]
adverse effects with low CE50 values, such as sup-
pression of endogenous cortisol, might also be
greater (figure 4). This simulation is in agreement
with measured concentrations and effects after fractionated
dose administration. Administration of
twice-daily dose fractions increased the immunosuppressive
efficacy of methylprednisolone (biomarker:
T helper cell suppression) while it did not
increase short-term adverse effects (biomarker: insulin
and glucose), except for endogenous cortisol.
[64]
6.3.4 Adverse Effects
The CE50 for glucose induction is higher than the 100
CE50 for lymphocyte suppression. [3,65] Thus, if a
smaller daily dose is possible, e.g. with administration
of twice-daily doses, the overall effect of gluco-
50
corticoids on glucose metabolism should be less.
The degree and duration of endogenous cortisol
0
suppression is dose dependent. [7] However, it is unclear
whether the degree of short-term cortisol suppression
correlates with adrenal atrophy and limited
adrenal reserve or not. [215]
50
Methylprednisolone (µg/L)
7. Clinical Aspects of
Glucocorticoid Therapy
Clinically, glucocorticoid dosage practice can be
divided into five categories. These are low dose
(≤7.5mg prednisolone equivalent per day), medium
dose (>7.5mg, but ≤30mg prednisolone equivalent
per day), high dose (>30mg, but ≤100mg prednisolone
equivalent per day), very high dose (>100mg
prednisolone equivalent per day), and pulse therapy
(≥250mg prednisolone equivalent per day for one or
a few days). The first three categories were estimated
to correspond to

86 Czock et al.
macodynamics (e.g. includes additional nongenom- methylprednisolone pulse therapy. [283,284] In a retroic
mechanisms) compared with maintenance immu- spective study of diffuse alveolar haemorrhage assonosuppression.
Clinically, the effect of glucocorti- ciated with bone marrow transplantation, only very
coid pulses is more similar to an all-or-none high doses of glucocorticoids were effective. [285]
principle than to a steady function of dose. Some
Treatment with dexamethasone has been sugdiseases
(other than those requiring emergency thergested
for acute CNS diseases. [286,287] Dexamethapy)
are treated intermittently with glucocorticoid
asone is usually preferred for treatment of CNS
pulses in order to maximise the beneficial effects as
diseases, because penetration into cerebrospinal fluwell
as to minimise adverse effects.
id is superior compared with prednisolone, as shown
Glucocorticoid pulses are usually administered
in a nonhuman primate model. [288]
intravenously. However, very high oral doses (≥1g)
of prednisolone (as tablets) and methylprednisolone
7.1.2 Non-Emergency Treatment
succinate (as an oral solution) had maximum concentrations
and area under the plasma concentramanagement
Glucocorticoids are a standard therapy for the
of acute SLE. [289,290] Despite an in-
tion-time curves (AUCs) similar to those after
intravenous administration. [15,275,276] Therefore, oral
creased risk of infections with glucocorticoid treatadministration
of glucocorticoids might be investiprednisolone
ment, overall survival is improved. [291] Methyl-
gated for some indications.
pulses are effective [292] and there was a
more rapid improvement in renal function following
7.1.1 Emergency Treatment
pulse methylprednisolone therapy in lupus nephritis
[293,294] while adverse effects were not in-
Antirejection therapy with intravenous glucocorcreased.
In patients with nonrenal lupus
ticoid 1000mg pulses was first reported in patients
erythematosus, life-threatening manifestations such
with kidney transplants. [277] The clinical response of
as coma, seizures or thrombocytopenia responded
antirejection treatment correlated with the induction
better to methylprednisolone pulses than to oral
of apoptosis of infiltrating lymphocytes. [278] This
glucocorticoid protocols.
mechanism might contribute to the fast clinical ef-
[296]
fect on the patient’s symptoms and objective paragroup
Primary glomerulonephritis is a heterogeneous
meters such as transplant size after such pulses.
of diseases that can lead to the nephrotic
Crescentic rapidly progressive glomerulonephritis
syndrome, chronic renal failure or both. IgA nephritis,
mainly the type not due to antiglomerular basement
can be treated with methylprednisolone pulses
membrane antibodies, was treated successfully (1000mg for 3 days) every 2 months. The mainten-
with methylprednisolone intravenous pulse therapy ance dose is administered orally on alternate
(1000 mg/day for 3–5 days [279] or 7 days [280] ). days. [297] Previous studies that did not use glucocor-
Atheroembolic renal disease, caused by cholestic
ticoid pulses were unable to demonstrate a therapeuterol
emboli, is associated with eosinophilia and
effect of glucocorticoids in IgA nephritis. In
vasculitis-like histological appearance [281] and was severe idiopathic childhood nephrotic syndrome,
effectively treated by methylprednisolone pulses methylprednisolone 1g/1.73m 2 pulses induced a
(500mg for 3 days), followed by oral prednisone 0.5 more rapid remission of proteinuria than oral predmg/kg/day.
[282]
nisolone. [298]
Patients with diffuse alveolar haemorrhage due to Glucocorticoids are a standard therapy for the
SLE, systemic vasculitis or anti-GBM (glomerular management of multiple myeloma. Very high-dose
basement membrane) nephritis such as Goodpasrelapsed
methylprednisolone has been used in refractory or
ture’s syndrome were treated effectively with
[299]
multiple myeloma.
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

Pharmacokinetics/Pharmacodynamics of Glucocorticoids 87
7.2 Diseases Not Treated with Pulse Therapy twice-daily administration in glucocorticoid replacement
therapy. [313]
Rheumatoid arthritis is characterised by the acsystemic,
Maintenance therapy of asthma is based not on
cumulation and persistence of inflammatory cells in
but on local (inhaled) glucocorticoid ad-
synovial joints, which results in joint damage. The ministration. [242,246] A more frequent administration
anti-inflammatory and antiproliferative effects of of budesonide (four times daily vs twice daily) was
glucocorticoids [300] leads to a reduced rate of joint superior in patients with moderate to severe asth-
destruction. [301]
ma. [314]
Systemic glucocorticoids are used in the treatment
of acute asthma. Oral treatment was similarly 7.4 Variation in Clinical Response to
effective compared with intravenous methylprednisolone
Glucocorticoid Therapy
pulses. [302] Very high doses of hydro-
cortisone provided no benefit compared with lower The clinical response to glucocorticoid treatment
doses. [303] Methylprednisolone is often preferred for varies considerably between patients. This variabiltreatment
of lung diseases because it achieves higher ity can be due to pharmacokinetic properties, pharconcentrations
in the lung compared with prednisoticoid
clearance could lead to lower exposure to the
macodynamic properties, or both. Higher glucocor-
lone (as measured in bronchoalveolar lavage fluid of
rabbits). [304]
drug and consequently to lower immunosuppressive
Severe sepsis and the adult respiratory distress
and anti-inflammatory action. For example, patients
syndrome involve an uncontrolled host defence resrejection
had a shorter methylprednisolone half-
with kidney transplants who experienced transplant
ponse that includes inflammation, endothelial damlife.
age, enhanced coagulation, microthrombi and relative
[315]
adrenal insufficiency. [305] Treatment with very A correlation between the clinical response and
high bolus doses of methylprednisolone for 24 hours the in vitro responsiveness of stimulated lympho-
did not improve mortality, [306,307] but prolonged cytes to glucocorticoid treatment has been observed.
treatment with stress-dose glucocorticoids for days Such a correlation might be useful to predict the
to weeks was beneficial. [305,308,309]
clinical response in patients with focal and segmen-
tal sclerosing glomerulonephritis, [316] with kidney
transplants, [317,318] with asthma, [319] and with rheu-
7.3 Role of the Dosage Interval matoid arthritis. [320]
8. Conclusions
At one time, glucocorticoids were thought to be
qualitatively indistinguishable [321] because they act
via the same receptor, but today qualitative differ-
ences have been discovered. Many beneficial and
adverse effects of glucocorticoids are due to geno-
mic mechanisms, but there is growing evidence that
some glucocorticoid effects are mediated by nonge-
nomic mechanisms, especially with pulse glucocor-
ticoid therapy. As these mechanisms can differ between
the various glucocorticoids, one glucocorti-
coid cannot be simply replaced by another.
A twice-daily glucocorticoid dosage is recommended
clinically for treatment of severe diseases.
[310] Daily prednisolone produced more intensive
and longer sustained immunosuppressive effects
(biomarker: T cells) than alternate-day
treatment in kidney transplant patients. [311] Accordingly,
prolongation of the dosage interval should
lead to reduced effects. A prednisolone dosage regimen
of 90mg on alternate days was less effective
than 15mg every 8 hours in patients with giant cell
arteritis. [312]
Due to the short half-life of hydrocortisone, administration
three times daily might be superior to
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

88 Czock et al.
Pharmacokinetic/pharmacodynamic models are
useful for simultaneously analysing the pharmacokinetics
and pharmacodynamics of a drug and for
making predictions. For low-dose maintenance therapy
with glucocorticoids, twice-daily dose fractions
might allow a lower daily dose and possibly a reduction
in some adverse effects. Intravenous glucocorticoid
pulses can be given for some indications with a
dose interval of 4 weeks. New pharmacokinetic/
pharmacodynamic models for glucocorticoid pulse
therapy should be developed and evaluated.
Acknowledgements
This study was supported by the European Commission
within the PharmDIS project (BMH4-CT98-9548 and IST
Craft-2001-52107). The authors have no conflicts of interest
to disclose.
Appendix
Statistical Data Synthesis
Published pharmacokinetic parameters are heter-
ogeneous and their values vary between studies.
Therefore, a statistical data synthesis is necessary to
combine such values and estimate the population
mean. [322] In the current paper we summarised the
published values from different publications as the
pooled mean x where x , x , ...
1 2
xk
are the published
mean values and the total number of subjects n was
calculated as n = n 1 + n2 +…+ nk (equation 3).
Model for Simulation
We used an indirect response model for simula-
tion of twice-daily dose fractions of methylprednisolone
(figure 3 and figure 4). The pharmaco-
kinetic model was a one-compartment model with a
first-order formation rate and a first-order elimination
rate where MPs is methylprednisolone succi-
nate, MP is methylprednisolone, k f is the formation
rate constant, and ke is the elimination rate constant
(equation 5 and equation 6).
dMPs
kf MPs
dt
= - ·
dMP
dt
k
= ·
f
MPs
k
- ·
e
MP
(Eq. 5)
(Eq. 6)
The pharmacodynamic model for T helper cell
suppression was a precursor-dependent indirect response
model as developed by Sharma et al. [273] and
Booker et al. [30] ThE are extravascular T helper cells
and Th are blood T helper cells. The rate constant kin
describes formation of new T helper cells, the timevarying
rate constant kp(t) describes the migration of
T helper cells from the extravascular to the blood
compartment, the rate constant kout describes the
removal of T helper cells, and I(t) describes the
inhibitory effect of glucocorticoids on cell migration
(equation 7 and equation 8).
dThE
= kin
- kp
( t)
· I(
t)
· ThE
dt
dTh
= kp
( t)
I(
t)
dt
· ·
ThE
-
k
·
out
Th
(Eq. 7)
n1
x n x n x
x
· 1
+ 2
· 2
+ … + k · k
=
(Eq. 8)
n
The inhibitory function I(t) for the effect of
(Eq. 3) methylprednisolone was an E max model where para-
The pooled standard deviation was calculated meter Emax is the maximum achievable effect and
using the published standard deviations s1, s2, …sk parameter CE50 is the concentration producing the
(equation 4). half-maximal effect (equation 9).
2
2
2
( ) ( ) ( ) ½
é s1 n1
−1
+ s2
n2
−1
+ … + sk
nk
-1
ù
s =
ê
ú
ë
n - k
û
I(
t)
=
1
-
E
CE
·
max
50
+
MP(
t)
MP(
t)
(Eq. 4) (Eq. 9)
© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (1)

Pharmacokinetics/Pharmacodynamics of Glucocorticoids 89
For the migration of T helper cells from the pharmacodynamic parameters for cortisol suppresextravascular
to the blood compartment a periodic sion: CE50 = 0.446 µg • L –1 , Emax = 1; system
function was applied where Rm is the mean input parameters of cortisol variation: kout = 0.338 h –1 ,
rate, Rb is the amplitude and tz is the peak time in tmin = 12.2 hours (24-hour clock), tmax = 21.4
relation to time zero (equation 10).
hours (24-hour clock), Rm = 23.5 µg • L –1 • h –1 , Rb
é 2π
ù
= 22.5 µg • L –1 • h –1 .
k = + · ( - ) ·
p
( t)
Rm
Rb
cos t t
ê z ú
24 û
ë
k ( t)
in
k ( t)
in
=
=
R
R
m
+
t = T min to T max
=
m
+
R
m
+
R
·
b
·
b
t = T max to 24 hours
k ( t)
in
R
R
é 2π
( t
cos
2
ê
ë
ê
ë
é2π
cos
·
b
cos
é
ê
·
ë2
24
T )
24)
· + -
max
·(
Tmin
- Tmax
+
( t
2
T
T
ù
ú
û
(Eq. 12)
· - ·
min
-
max
ù
ú
2 · ( Tmax
- Tmin
)
û
2π
( t
( T
T
· -
max
min
- Tmax
+
)
)
24)
(Eq. 13)
ù
ú
û
(Eq. 10) References
The pharmacodynamic model for cortisol sup-
pression used the same inhibitory function I(t). The 510-8
time-varying secretion of cortisol was described by
kin(t) and the elimination of cortisol by the rate
18-31
constant kout (equation 11).
dCort
= kin
( t)
· I(
t)
- k ·
out
Cort
dt
(Eq. 11)
The input function kin(t) for secretion of cortisol
was a dual cosine model that also allows for asymmetric
inputs where Tmax and Tmin are the timepoints
where the secretion is maximal and minimal, respectively
(equations 12, 13 and 14).
t = 0 to T min
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