PHARMACOKINETICS OF SSRI ANTIDEPRESSANTS

PHARMACOKINETICS OFSSRI ANTIDEPRESSANTSAlphonse Poklis, Ph.D., ABFTProfessor, PathologyPharmacology & ToxicologyChemistry & Forensic ScienceSchool of MedicineVirginia Commonwealth UniversityRichmond, VA 23298-0165

Selective SerotoninReuptake Inhibitors (SSRI)• Citalopram (Celexa, Cipramil, Seropram)Escitalopram (Lexapro)• Duloxetine (Cymbalta)• Fluoxetine (Prozac)• Fluvoxamine (Luvox)• Paroxetine (Paxil)• Sertraline (Zoloft)• Venlafaxine (Effexor)

Drug # Cases % Case Mode Range UnitsBlood Alcohol 2230 76.3 0.12 0.01 - 0.40 gm %THC 345 12.0 0.001 0.500 mg/L

Toxicology Findings, 43 yr Woman:• Drugblood,mg/L Liver, mg/Kg• Hydrocodone 0.09• Methadone 1.2 12• Bupropion 0.4• Fluoxetine 0.7 40• Amitriptyline 0.6 26• Nortriptyline 1.4 36• Quetiapine

Antidepressant Drugs:Pharmacokinetic Consideration• Large Apparent volume of distribution• Chiral drugs• Active metabolites• BiotransformationInteractions with CYP450isoenzymes

DISPOSITION OF DRUGSThe disposition of chemicals entering the body (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5thed., New York: McGraw-Hill, 1996).

DosagePlasmaConcen.Site ofActionEffectsPharmacokineticsPharmacodynamics

Drug Plasma ProfilePlasma concentration141210864200 5 10 15 20TIME (hours)

LOCUS OF ACTION“RECEPTORS”TISSUERESERVOIRSBound Free Free BoundABSORPTIONFree DrugEXCRETIONBound DrugSYSTEMICCIRCULATIONBIOTRANSFORMATION

LOCUS OF ACTION“RECEPTORS”TISSUERESERVOIRSBound Free Free BoundABSORPTIONK AFree DrugK EEXCRETIONBound DrugSYSTEMICCIRCULATIONK MBIOTRANSFORMATION

Pharmacokinetic Data• Bioavailability(%)• Volume of distribution (L/Kg)• Bound in plasma (%)• Distribution Ratio of [plasma]/[blood]• Plasma half-life life (hr)• Clearance (mL/min/Kg)• Urinary excretion (%)

Pharmacokinetic Data• Single dose peak plasma concentration• Effective steady state plasma concentration• Toxic plasma concentration• Life threatening or lethal bloodconcentration

BioavailabilityDestroyedin gutNotabsorbedDestroyedby gut wallDestroyedby liverDosetosystemiccirculation

BioavailabilityDefinition: the fraction of the administereddose reaching the systemic circulationfor i.v.: 100%for non i.v.: ranges from 0 to 100%e.g. lidocaine bioavailability 35% due todestruction in gastric acid and liver metabolismFirst Pass Effect

Log Plasma concentration10050201050OralIVBioavailability = (AUC) Oral(AUC) IV0 5 10 15 20TIME (hours)

Apparent Volume of DistributionDrugs appear to distribute in the body as if it werea single compartment. The magnitude of the drug’sdistribution is given by the apparent volume ofdistribution (V d ).V d =Amount of drug in bodyConcentration in PlasmaV d = Dose/C 0

Gradient Between Drug in Bloodand Drug in Other Tissues & FluidsVd = 1 L/Kg, in 70 Kg man = 70LIf 70mg dose, then 70mg/70L/Kg = 1 mg/L in bloodDistributionTotal drug in blood/total drug in body tissues = 4mg/66mgVd = 10 L/Kg, in 70 Kg man = 700LIf 70mg dose, then 70mg/700L/Kg = 0.1 mg/L in bloodDistributionTotal drug in blood/total drug body tissues =0.4mg/69.6mg

Examples of apparent Vd’s forsome drugsDrug L/Kg L/70 kgSulfisoxazole 0.16 11.2Phenytoin 0.63 44.1Phenobarbital 0.55 38.5Diazepam 2.4 168Digoxin 7 490

Hemodialysis• Rate of toxicant removal related to Blood flow through dialyzer Dialysate flow rate Drug solubility Permeability of membranes, surface >2M 2• Disadvantages Infections Blood clots, hematomas Complex apparatus, skill personnel

Dialysis Clearance• Dialysis clearance = E x B x S• Where E = extraction ratio = Ca – Cv/Ca Where; Ca is concentration of toxicant inarterial blood Cv is concentration of toxicant in venousblood B = blood flow (300 mL/min) S = serum factor (1-hematocrithematocrit)

Hemodialysis Pharmacokinetics• Dialyzer flow rate, 300 mL/min• If Extraction ratio = 1, to totally clear blood(5000 mL) of agent where;Ke = 300 mL/min /5000 mLKe = 0.06/min (~6%)T1/2 = 0.0693 / 0.06/ min = 11.6minTotal removal = 5 x T1/2 = 58 min

Hemodialysis PharmacokineticsClearance of Methanol• Dialyzer flow rate, 300 mL/min• If Extraction ratio = 1, to totally clear blood (5000mL) of agent where; Vd = 0.6L/Kg, 70Kg man Ke = 300 mL/min /42000 mL Ke = 0.007/min (~0.7%) T1/2 = 0.0693 / 0.007/ min = 99min Total removal = 5 x T1/2 = 495 min (~8 hours)

Hemodialysis PharmacokineticsClearance of Phenytoin• Dialyzer flow rate, 300 mL/min• If Extraction ratio = 1, to totally clear blood (5000mL) of agent where; Vd = 0.8L/Kg, 70Kg man Ke = 300 mL/min /56000 mL Ke = 0.005/min (~0.5%) T1/2 = 0.0693 / 0.005/ min = 138min Total removal = 5 x T1/2 = 690 min (~11.5 hr)

Hemodialysis PharmacokineticsClearance of Amitriptyline• Dialyzer flow rate, 300 mL/min• If Extraction ratio = 1, to totally clear blood (5000mL) of agent where; Vd = 10L/Kg, 70Kg man Ke = 300 mL/min /700,000 mL (700L) Ke = 0.0004/min (~0.04%) T1/2 = 0.0693 / 0.0004/ min = 173min (~2.9 hr) Total removal = 5 x T1/2 = 866 min (~14.4 hr)

Hemodialysis PharmacokineticsClearance of Fluoxetine• Dialyzer flow rate, 300 mL/min• If Extraction ratio = 1, to totally clear blood (5000mL) of agent where; Vd = 30L/Kg, 70Kg man Ke = 300 mL/min /2,100,000 mL (2,100L) Ke = 0.00014/min (~0.014%) T1/2 = 0.0693 / 0.00014/ min = 495min (~8.3 hr) Total removal = 5 x T1/2 = 2,475 min (~41.25 hr)

LOCUS OF ACTION“RECEPTORS”TISSUERESERVOIRSBound Free Free BoundIV injectionFree DrugK EEXCRETIONBound DrugSYSTEMICCIRCULATIONK MBIOTRANSFORMATION

First Order EliminationdC/dt related CdC/dt = – kCC t =C 0 . e – K E tlnC t = lnC 0 –K E tlogC t= logC 0 – K E t2.303y = b –mx

Plasma Concentration Profileafter a Single I.V. InjectionLog Plasma Concentration100001000100101Distribution and EliminationC 0Distribution equilibrium0 1 2 3 4 5 6TimeElim ination only

Log Plasma Concentration10000 First Order Elimination1000 logC 0100Slope = -K E1010 1 2 3 4 5 6TimelogC t = logC 0 –K e t/ 2.303

Plasma Elimination Rate ConstantK E is the fraction of drug continuouslyremoved from plasma (blood)per unit time (hr).Thus; if K E = -0.25/hr, the plasma drugconcentration is continuouslydeclining by ~25%

Plasma Elimination Rate ConstantK E= the sum of all rate processes thatremove the drug from plasma.K E = K M1 + K M2 + K U + K othersWhere; K M1 = rate of formation ofmetabolite 1K M2 = rate of formation of metabolite 2K U = rate of urinary excretionK others = rate of other processes, ex sweat,

Fluvoxamine MetabolismF 3N O NH 2OCH3Km3F 3N O OHKm1F 3N O NH 2COOHKm2OCH3F 3N OH OCH3Overmars et al European J Drug Pharmacok 8:269-280,1983

Eliminationof drugs from the bodyMAJORMINORKIDNEYfiltrationsecretion(reabsorption)LUNGSexhalationLIVERmetabolismsecretionOTHERSmother's milksweat, saliva etc.

The plasma half-lifeis the time for the plasma concentration todecline to half the original concentrationlnC t = lnC 0 –K E tWhen: lnC t = lnC t1/2lnC 0 = lnC 0t = t 1/2T 1/2 = 0.693/K E

Plasma Half-LifeLog Plasma Concentration100001000100501CpCp/2t 1t 1/2 = 4 hrs t 20 1 2 3 4 5 6Time

First Order EliminationClearance: volume of plasma cleared ofdrug per unit time.• Clearance:Clearance = Rate of eliminationPlasma concentration

Plasma ClearanceRate of elimination = K E x Amount in bodyRate of elimination = CL x [Plasma]Therefore,K E x Dose = CL x [plasma]K E = CL/V dV d K E = CL0.693 V d / t1/2 = CL

Plasma ClearanceClearance is used to determine iv infusion ratesC ss CL = dosing rateExample, lidocaineCL = 11 mL/min/Kg, in 70 Kg man = 0.8 L/min/KgCss = 3mg/LDosing rate = 0.8L/min/Kg x 3mg/L = 2.4 mg/min

LOCUS OF ACTION“RECEPTORS”TISSUERESERVOIRSBound Free Free BoundABSORPTIONK AFree DrugK eEXCRETIONBound DrugSYSTEMICCIRCULATIONK MBIOTRANSFORMATION

Multiple dosing• On continuous steady administration of a drug,plasma concentration will rise fast at first thenmore slowly and reach a plateau, where:• rate of administration = rate ofie. . steady state is reached.elimination

Plasma Concentration64321684210Steady State Concentration0 5 10 15 20 25 30Time

Steady StatePlasma Concentrations• Obtained after dosing for 5 half-liveslives• After drug administration is stopped,requires 5 half-lives lives to decline to zero

Steady StatePlasma Concentrations• Doseafter dose after 1 half-life• 1 100 50• 2 150 75• 3 175 88• 4 188 94• 5 194 97• 6 197 98

C ss = F (dose)/ V d K e TC ss = 1.44 F (dose) t 1/2 / V d TC ss = Plasma Steady State ConcentrationF = BioavailabilityV d = Volume of distributionK e = Plasma elimination rate constantT = Dosage intervalt 1/2 = Plasma half-life

Pharmacokinetic parameters• Volume of distribution V = DOSE / C 0• Plasma clearanceCl = K E .V d• plasma half-lifelife t1/2 = 0.693 / K E• Bioavailability(AUC) x / (AUC) iv

Variability in Drug Metabolism60Plasma DrugConcentration (mg/L)504030201000 5 10 15Daily Dose (mg/kg)

Antidepressant Drugs:Metabolism Consideration• The metabolism rate for antidepressants can varydue to cytochrome p450 isoenzymes• Genetic polymorphisms exist that may classify aperson as a “poor metabolizer” of a given p450enzyme. (i.e. CYP 2D6, CYP 2C19)• Certain drugs may inhibit the production of aparticular enzyme or may compete with anenzyme, thus making an individual a poormetabolizer

Cytochrome P-450 CycleR-OH or epoxide[P-450 (Fe +3 )]RH substrate[P-450 (Fe +3 )] [RH][P-450 (Fe +3 )] [RH]H 2OOe-via NADPHplus a reductaseenzyme2H+[P-450 (Fe +2 )] [RH][P-450 (Fe +2 )] [RH]O 2=[P-450 (Fe +2 )] [RH]Oxygene-via NADPHor NADHplus a reductaseenzymeO 2

Cytochrome P-450: Oxidative• Structural diversity due toNonspecificityIsozymesIsozymes - multiple forms of an enzyme• Enzymes are “inducible” by various chemicals• Exposure increases the rate of enzymeproduction

Cytochrome P-450: Oxidative• Isozymes differ in protein structure Different amino acid sequences Produce different 3-D 3 D structures Drug bound to the protein portion• Remember: All activated oxygen chemistry occurs at theiron center heme with oxygen transfer to theprotein bound substrate

Polymorphism in ClinicalPharmacology• Drug metabolism enzymes Cytochrome P450's (CYP) NAD(p)H quinone oxidoreductase N-acetyl transferase (NAT) Thiopurine methyltransferase (TPMT)• Receptor proteins α 2 -Adrenergic receptor Dopamine D3-receptor

Genetic Polymorphism• Structural variations of a gene (Allele)Mendelian inheritance Homozygous: Two common or twovariant alleles Heterozygous: One common and onevariant allele Recessive: Must be homozygous to revealphenotype Dominant: Heterozygous genotypedisplays variant phenotype

Mechanisms of polymorphism• Single nucleotide Coding region Non-coding regionRegulatory sequencesIntron• Gene deletion, duplication

Cytochrome P450 Nomenclature• CYP’s that have 40% or greater sequencehomology are classified as the same family• Enzymes with 55% or greater sequencehomology are classified in the samesubfamily• CYP2D6 is the abbreviation for the CYP infamily 2, subfamily D, gene product 6

NomenclatureCytochrome P450 2 D 6 *4SuperfamilyFamilySubfamilyIsoenzymeAllele Variant

HepaticCytochrome P450 Content2C24%2D63%'2E19%1A218% 2A65%2B61%3A40%

Cytochrome P450 Isoenzymes• It has been reported that for drugs that undergooxidative biotransformation 50% metabolized by CYP 3A3/4 30% metabolized by CYP 2D6 10% metabolized by CYP 2C9/10 4% metabolized by CYP 1A2 2% metabolized by CYP 2C19 2% metabolized by CYP 2E1

Cytochrome P450 2D6• Polymorphism – none or have less than normalamounts 5-10% of Caucasians– poor metabolizers ~1% of Asian – poor metabolizers• Many important hydroxylation reactions antidepressants, antipsychotics, , analgesics, &cardiovascular drugs• 2D6 can be inhibited by drugs Not necessary for drug to be substrate to inhibitP450• Autoinhibition

Cytochrome P450 2D6SubstratesSSRITCA’sAntipsychoticsBeta-BlockersBlockersCodeineTramadolDextromethophanEncainideFlecainideInhibitorsSSRIClomipramineBupropionCimetidineChlorpromazine,CocaineMethadone,DoxorubicinHaloperidolQuinidine

SSRI InhibitorsCytochrome P450 2D6• Weak to Moderate Inhibitors Citalopram Duloxetine Fluvoxamine Sertraline• Potent Inhibitors Fluoxetine Norfluoxetine Paroxetine

Cytochrome P450 3A4SubstratesAnalgesicsAntiarrhythmicsAntidepressants-SSRIsBenzodiazepinesCalcium antagonistsCocaineLovastatinMacrolide antibioticsOmeprezoleInhibitorsSSRIsCimetidineDiltiazemGrapefruit juiceKetoconazoleVerapamil

Inducers of Cytochrome P450 3A4• Barbiturates• Carbamazepine• Glucocorticoids• Phenytoin• Rifampin• St. John’s wort

SSRI InbibitorsCytochrome P450 3A4• Weak InhibitorCitalpramFluoxetineParoxetineSertraline• Potent InhibitorNorfluoxetineFluvoxamine

Michaelis-MentenMenten KineticsV maxVV = V max ( [S] / [S] + K m )If [S] >>> Km, V = VmaxK mIf Km >>> [S], V = constant [S]00[S]

Reciprocal Michaelis-MentenMenten1/V = 1/V max + K m /V max X 1/[S]1/VSlope = K m /V maxIntercept y-axis = 1/VIntercept onx-axis = -1/ K m1/[S]

Competitive Enzyme Inhibition1/V = 1/V max + K m /V max (1 + 1/K 1 )(1/[S])Where, K 1 is the dissociation constant of theenzyme-inhibitor complexIn the presence of an inhibitor, the slopeincreases by the factor (1 + 1/K 1 )K m is increasedV max is unaltered

Competitive Enzyme InhibitionCompetitive inhibitor1/VNo inhibitor present1/[S]

Factors Complicating Interpretationof Postmortem Blood Concentrations• Large individual variations in pharmacokineticparameters in therapeutic situations• Alterations in pharmacokinetics in overdose Saturation of biotransformation & elimination Non-equilibrium distribution• “postmortem release” of tissue bound drugs intoblood after deathA. Poklis, Internat Assoc Forensic Sci, Vancouver, 1987

Postmortem Blood toCalculate DoseIf V d is low, then V d = Dose/C 0If V d is high, thenC b V d does not = Dose

Selective SerotoninReuptake Inhibitors (SSRI)• Citalopram (Celexa, Cipramil, Seropram)Escitalopram (Lexapro® )• Duloxetine (Cymbalta)• Fluoxetine (Prozac)• Fluvoxamine (Luvox)• Paroxetine (Paxil)• Sertraline (Zoloft)• Venlafaxine (Effexor)

Variability in Pharmacokinetics60Plasma DrugConcentration (mg/L)504030201000 5 10 15Daily Dose (mg/kg)

SSRI Metabolism• Inhibit metabolism of other drugs• Autoinhibition:inhibit their own metabolismnon-linear relationship between dose andblood concentrationincrease blood half-life life with increasingdoses

SSRI’s That Exhibit Autoinhibition• Fluoxetine & norfluoxetine• Fluvoxamine• Paroxetine

CitalopramH 3CON CH 3F

Citalopram• Dosage: 20-60 mg/day• Bioavailability 80%• Fb: : 0.80• Time to Peak: ~4 hr• Vd: : 12-16 16 L/kg•t ½ : 25-35 hr• Time to Steady State: 6-767 days

Citalopram• Biotransformation Desmethycitalopram CYP3A4 / CYP2D6 /CYP 2C19 Didesmethycitalopram, CYP 2D6• Active Metabolite: Desmethycitalopram (25-50%f parent) Didesmethycitalopram (10% of Parent)• % excreted in urine: citalopram 12% desmethycitalopram 5%

Citalopam• Very weak inhibitorCYP 3A4CYP 2B6CYP 2C9CYP 2D6CYP 2C19• Elderly, increased half-lifelife• Hepatic disease – little effect• Renal disease – little effect

CITALOPRAM METABOLISMC H 3HONCH3ON CH 3FOHNHFdesmethylcitalopramN-didesmethylcitalopramF

Citalopram & QuetiapineAbundance150000014000001300000120000011000001000000900000800000AlpraprodineTIC: 10607.DCitalopramQuetiapine MetaboliteQuetiapine700000600000500000400000300000200000100000Time-->10.00 11.00 12.00 13.00 14.00 15.00 16.00 17.00 18.00

Abundance50000045000040000035000030000025000020000015000010000050000Time-->Citalopam & OthersTIC: 6061.DIstdCaffeineNorfluoxetineTramadolO-DesmethlyramadolNortriptylineDiazepamCitalopram9.50 10.00 10.50 11.00 11.50 12.00 12.50 13.00 13.50 14.00

Citalopram Serum Values• Single- and multiple-doses both producelinear and dose proportional effectswithin the 10-60 mg/day prescription• Therapeutic valuecitalopram50-100 ng/mLdesmethycitalopram15-40 ng/mL• Toxic Concentration > 1,000 (?)

Citalopram IsomersH 3CH 3CON CH3ON CH 3F•“S”“S” and “R” isomers (racemic(mixture)•“S”“S” isomer 2-424 times SSRI then “R”F

Citalopram Enantiomers in FemoralBlood, 53 Postmortem Cases• Citalopram Mean S isomer 1.53 ug/mL, SD = 3.57 Mean R isomer 1.72 ug/mL, SD = 3.58 S/R = 0.67, SD 0.25• Desmethylcitalopram Mean S isomer 0.14 ug/mL, SD = 0.21 Mean R isomer 0.20 ug/mL, SD = 0.22 S/R = 0.68, SD 0.20Holmgren et al J. Anal. Toxicol. 26:94-104,2004

Escitalopram• “S” isomer citalopram)• 10 mg = 20-40 mg citalopram

Escitalopram CYP 450• R & S isomers metabolized by same P450• Substrate:CYP 2C19CYP 3A4CYP 2C19• Weak inhibitor:CYP 2D6

DuloxetineOSN CH 3H

Duloxetine• Dosage: 40-120 mg/day• Bioavailability ?• Fb: : 95%• Time to Peak: ~4 hr• Vd: : Mean 27 L/Kg (13-50 L/kg)•t ½ : 6 -19 hr• Time to Steady State: 3-535 days

Duloxetine Elimination• Biotransformation Extensive ring hydroxylation O-Methylation Glucuronide & sulfate conjugation• Plasma metabolites as glucuronides: 4-hydroxy-duloxetine 5,6-hydroxy-duloxetine 6-hydroxy-5-methoxy duloxetine 4,6-dihydroxy-duloxetine• Radioactivity excreted in urine: 72% in 13 days• Radioactivity excreted in feces: 18% in 13 days

Duloxetine Metabolism• Substrate:CYP 2D6 CYP 1A2• Bioavailability reduced by 1/3 in smokers• Elderly, no significant change in half-lifelife• Moderate inhibitorCYP 2D6

Duloxetine Plasma MetabolitesLanz et al. Drug Metab. Dispos. 31:1142,2003OHOHOHSON CH 3HOHSON CH 3H6-hydroxyO CH 3OHSON CH 3HCatecholOHOOS4,6-hydroxyN CH 3HSN CH 3H5-hydroxy-6-methoxy

Duloxetine Urine Metabolites11 hydroxylated and hydroxy-methoxy metabolitesExcreted as glucuronide and sulfate conjugatesO CH 3OSO 3OOGlucuronideON CH 3N CH 3SHSH10 – 16%13 – 21%

Duloxetine Serum Steady-StateTrough Values• Twelve healthy adult men• Dose 20 mg bid 12ng/mL (2 – 12ng/mL)• Dose 30 mg bid 20 ng/mL (10 – 48 ng/mL)• Dose 40 mg bid 30 ng/mL ( 12- 40 ng/mL)• Generally trough serum values > 5 ng/mL predictssustained inhibition of 5-HT 5reuptake.Sharma et al J Clin. Pharmacol. 40:161,2000

FluoxetineOHNCH3F 3C

Fluoxetine• Dosage: 20-80 mg/day• Fb: : 0.94• Time to Peak: 6-868 hr• Vd: : 20-42 L/kg• Time to Steady State: 1 week – month• % excreted as parent in urine:

Fluoxetine StereoisomersF 3COHHNCH3F 3COHHNCH3Similar SSRI activity

Norfluoxetine StereoisomersOHHNHOHHNHF 3CF 3CS >>>> R in SSRI activity

FLUOXETINE METABOLISM• Biotransformation to norfluoxetine ismediated by CYP 2D6• 7% of population reduced CYP 2D6 activityS isomer metabolized slower tonorfluoxetine, , results in higher Flu/norfluR isomer normal rateAt steady-state state concentration of the 4parent-metabolite isomers equalNo pharmacological difference

Fluoxetine CYP 450• Substrate:CYP1A2CYP 2B6CYP 2C8/9CYP 2C19CYP 2D6CYP 2E1CYP 3A4

Fluoxetine CYP 450• Moderate to severe inhibitor:CYP 1A2CYP 2B6CYP 2C8/9CYP 2C19CYP 2D6CYP 3A/4• Norfluoxetine: : Inhibitor of 3A3/4 (potent)

FLUOXETINE METABOLISMOHNCH3OHNHF 3CF 3COHNorfluoxetineF 3CTrifluoromethylphenol

Fluoxetine / NorfluoxetineAbundance320000030000002800000260000024000002200000200000018000001600000140000012000001000000800000600000400000200000ISTDfluoxetinenorfluoxetinedoxylaminedextromethorphanTIC: 9130.DoxycodoneFentanylTime-->10.0010.5011.0011.5012.0012.5013.0013.5014.0014.5015.0015.50

Fluoxetine Half-life•t ½ : 24-72 hr (dose dependent)short term doses 1-13 dayslong term doses 4 - 6 days•t ½ : norfluoxetine (1 st order)short short term doses 4 - 16 dayslong long term doses 4 - 16 days

FLUOXETINE METABOLISM• Half-life life increased with hepatic disease• Half-live live not influenced byDecreased renel functionEderlyPediatric patients

Fluoxetine Serum Values• Single 40 mg dose = 15-55 55 ng/mL• 40 mg/day for one weekFluoxetine 91 – 300 ng/mLNorfluoxetine 72 –260 ng/mL• 40 mg/day for one monthFluoxetine 47 - 470 ng/mLNorfluoxetine 52 - 450 ng/mL

Fluoxetine Serum Values• Large variation in peak and trough concentrationsdependent upon Dose Dosage regiment Co-administration of other drugs• Therapeutic values fluoxetine, , ~ 100 - 500 ng/mL norfluoxetine, , ~100 - 450 ng/mL• Toxic Concentrations Fluoxetine >1,500 ng/mL (?)

Desipramine• Dosage: 25-300 mg/day• Fb: : 0.95• Time to Peak: 3-636 hr• Vd: : 22-59 L/kg•t ½ : 12-54 hr• Time to Steady State: 2-828 days

DESIPRAMINE METABOLISMHONHiminodibenzylCYP3A4NNHCH 3N10-OH-desipramineNHCH 3NCYP2D6NOHnordesipramineNH 22-OH-desipramineNHCH 3

Metabolism of Desipramine• Mediated by CYP1A2, CYP3A4, CYP2C19Desipramine 10-OHOH-Desipramine• Mediated by CYP2D6Desipramine 2-OH-Desipramine

Fluoxetine/Desipramine• Chronic administration20 mg/day fluoxetine50 mg/day desipramine• Desipramine plasma values increased 4Xwith concomitant fluoxetine• Desipramine plasma values still elevated 3weeks after fluoxetine discontinued

FluvoxamineF 3N O NH 2OCH3

Fluvoxamine• Dosage: 100-200 mg/day• Fb: : 0.77• Time to Peak: 2 -88 hr• Vd: : 25 L/kg•t ½ : 8-248hr (dose dependent >200mg)• Time to Steady State: 2-424 days

Fluvoxamine Elimination• Extensively biotransformedOxidation,deaminationN-O O cleavage N-acetylated• % excreted as parent in urine: ~3%• Therapeutic Concentration ~200 ng/mL• Toxic Concentration >2,500 ng/mL (?)

Fluvoxamine CYP 450• Substrate:CYP1A2CYP 2D6• Moderate to Severe Inhibitor:CYP 1A2CYP 2B6CYP 2C8/9CYP 2C19CYP 2D6CYP 3A/4

Fluvoxamine MetabolismF 3N O NH 2OCH3F 3N O NH 2COOHF 3N O OHOCH3F 3N OH OCH3Overmars et al European J Drug Pharmacok 8:269-280,1983

Fluvoxamine Metabolism, cont.F 3N O NH 2COOHF 3N O OHCOOHF 3N O OHOCH3F 3N O COOH OCH3COOHF 3N O COOHF 3N OH OCH3F 3N OH COOHF 3OCOOH

AbundanceTIC: 15763.D700000650000Fluvoxamine / Meperidine / TrazodoneISTD60000055000050000045000040000035000030000025000020000015000010000050000m-CCP meperidinenormeperidineCaffeineFluvoxaminepromethazineTrazadoneTime-->10.00 11.00 12.00 13.00 14.00 15.00 16.00 17.00 18.00 19.00

Fluvoxamine Serum Values• Single dose 100 mgPeak 31-87 ng/mL• Therapeutic Concentration ~200 ng/mL• Toxic Concentration >2,500 ng/mL (?)

ParoxetineFOOON

Paroxetine• Dosage: 10-50 mg/day• Fb: : 0.95• Time to Peak: 3-838 hr• Vd: : 5-285L/kg•Time to Steady State: ~ 1 week

Paroxetine Elimination• CYP 2D6 Polymorphism• Extensively biotransformed ring oxidative cleavage• t ½ : 7-377hr (dose dependent)fast fast met, ~ 16 hrslow slow met (7% population), ~ 41 hr• Parent excreted in urine:

Paroxetine & CYP 450Substrate: CYP2D6Moderate to serve Inhibitor CYP1A2 CYP 2B6 CYP 2C8/9 CYP 2C19 CYP 2D6 CYP 3A/4

PAROXETINE METABOLISMFFOOO CH 3OHOONNFFOHOCH 3OOHNN

Paroxetine /AmitriptylineAbundance190000180000170000160000150000140000130000TIC: 5282.Damitriptylinenortriptyline120000110000100000900008000070000600005000040000300002000010000alphaprodineparoxetineTime-->10.00 10.50 11.00 11.50 12.00 12.50 13.00 13.50 14.00 14.50 15.00

Paroxetine / MethadoneAbundance450000400000350000300000250000200000150000100000IstdMethadoneTIC: 6024.DChlorpheniramineParoxetine50000Time-->9.50 10.00 10.50 11.00 11.50 12.00 12.50 13.00 13.50 14.00 14.50 15.00

Paroxetine Serum Values• Single 20 mg dose peak• 1 – 33 ng/mL• 30mg/day, steady-state (15 subjects)*• Peak, average 62 ng/mL• Trough, aveage 31 ng/mL• Toxic Concentration• >300 ng/mL (?)Tasker et al Acta Psych. Scand.,Suppl. 350:152,1989.

SertralineHN CH 3ClCl

Sertraline• Dosage: 50-200 mg/day• Fb: : 0.99• Time to Peak: 6-868 hr• Vd: : 70 L/kg• Half-life:life:SertralineSertraline 22-36 hrNorsertraline60 –70 hr• Time to Steady State: 4-646 days

Sertraline Elimination• BiotransformedN-dealkylationring ring hydroxylation• Active Metabolite: norsertraline (20%f parent)• Metabolism decreasedHepatic diseaseElderly patients• % of parent excreted in urine:

Sertraline & CYP450 Isozymes• Moderate Inhibitor at high dosesCYP 2C19CYP 3A3CYP 3A4CYP 2B6CYP 2C19• Weak InhibitorCYP 2C8/9CYP 1A2CYP 2D6

SERTRALINE METABOLISMHN CH 3HN H ClCYP 3A4ClClClNorsertraline

Sertraline in Blood Extract DB-5AbundanceIstdTIC: 6476.DSerrtaline700000650000600000550000500000Norserrtaline450000400000350000300000250000200000150000Phthalate10000050000Time-->10.00 10.50 11.00 11.50 12.00 12.50 13.00 13.50 14.00 14.50

Methadone / Sertralinein Blood Extract DB-5Abundance2400000220000020000001800000160000014000001200000Alphaprodine, ISmethadoneTIC: 1507.Dsertralinenorsertraline1000000800000600000400000200000Time-->9.50 10.00 10.50 11.00 11.50 12.00 12.50 13.00

Sertraline Serum Values• Single dose average peak50 mg dose, ~10 ng/mL100 mg dose, 16 ng/mL200 mg dose, 56 ng/mL• Steady State average (range)50mg dose, 32 ng/mL (20 – 48)100 mg dose, 91 ng/mL (40 –187)200 mg dose, 206 ng/mL (99 – 309)

Risperidone MetabolismNNOCH 3 OHN CHN3NONNN OHONNOCH 3NNOFO9-HydroxyrisperidoneN CH 3NONOOHF2-HydroxyrisperidoneFNNOCH 3COOHF

Risperidone MetabolismNNNNOOOHCH 3N OCYP2D6Lesser CYP3A4FNCH 3NNO9-HO-risperidone , equipotentF

Risperidone PharmacokineticsCYP2D6 Polymorphism• Plasma half-lifelife SlowRisperidone9-HO-risperidone FastRisperidone9-HO-risperidone~20 hr~30 hr~3 hr~21 hr

Sertraline & Risperidone• Patients receiving 4 – 6mg/day, at 2 monthsaverage plasma concentrationRisperidone + 9-hydroxy 9risperidone53 +/- 12 ng/mL• Sertraline added 50mg/day after 2 monthsRisperidone + 9-hydroxy 9risperidone55 +/- 10 ng/mLSertraline range 22 – 43 ng/mLSpina et al Ther Drug Monit 26:386,2004

VenlafaxineCH 3H 3CNOHH C 3O

Venlafaxine• Dosage: 75-225 mg/day• Fb: : 0.99• Time to Peak: 2-424 hr• Vd: : 4-124L/kg•t ½ : venlafaxine 3-77 hro-methyl metabolite 9-139hr• Time to Steady State: 1-313 days

Venlafaxine Elimination• Biotransformed - polymorphismN-dealkylation O-dealkylation• Active Metabolite: O-desmethylvenlafaxineO• % excreted in urine: parent, 5% O-methylvenlafaxine, , 29-48% N-didesmethylvenlafaxine, , 6-19% 6 N-desmethylvenlafaxine, , 0.2-8%%

Venlafaxine CYP 450• Substrate:CYP 2C8/9CYP 2C19CYP 2D6CYP 3A/4• Inhibitor:CYP 2B6CYP 2D6CYP 3A/4

VENLAFAXINE METABOLISMH 3CCH 3NOHH 3CCH 3NOHC H 3OHOCH 3O-desmethylvenlafaxineHNOHHHNOHC H 3ON-desmethylvenlafaxineC H 3ON,N-didesmethylvenlafaxine

Venlafaxine & MetabolitesAbundance1100000ISTDTIC: 8811.D1000000900000800000700000600000500000400000300000200000100000venlafaxinen-desmethylvenlafaxineo-desmethylvenlafaxineMet ?diazepamnordiazepamTime-->10.00 10.50 11.00 11.50 12.00 12.50 13.00 13.50 14.00 14.50

Venlafaxine Steady-StateSerum Value• Steady state 150 mg/day, 50mg tid venlafaxine, , peak 194 ng/mL, SD 67 ng/mL venlafaxine, , trough 52 ng/mL, SD 38 ng/mL O-desmethyl, , peak 313 ng/mL, SD 118 ng/mL O-desmethyl, , trough 185 ng/mL, SD 67 ng/mL• Steady state 150 mg/day, 75mg bid venlafaxine, , peak 189 ng/mL, SD 54 ng/mL venlafaxine, , trough 56 ng/mL, SD 31 ng/mL O-desmethylpeak 308 ng/mL, SD 121 ng/mL O-desmethyl, , trough 194 ng/mL, SD 75 ng/mLTroy et al, J Clin. Pharmacol 35:404-409,1995

Venlafaxine Serum Value• Single 50 mg dose aveagevenlafaxine, , 70 ng/mL (2.2 hr)O-desmethylvenlafaxine, , 106 ng/mL (3.9 hr)• Toxic concentrations >5,000 ng/mL (?)• Postmortem blood concentrationsAve. 56 mgL (6 –89 mg/L)R.C. Baselt, Disposition Toxic Drugs & Chemicals in Man, 6ed, 2002

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