Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

262 Applying Pharmacogenomics in Therapeutics
therefore polymorphisms in drug-metabolizing enzymes and drug transporters that
alter the systemic exposure to the substrate drugs or active components of herbs may
affect the risk of interactions.
Case Report
A case report described an interaction of St. John’s wort (Hypericum perforatum)
with clozapine via inducing P450s, especially CYP1A2 and CYP3A4. A 41-year-old
woman with disorganized schizophrenia was stable on a fixed daily dose of 500 mg,
with stable plasma level (0.46–0.57 mg/L) of clozapine for the last six months.
However, it was revealed that she had started using St. John’s wort (three tablets
daily, 300 mg per tablet) shortly before the first measurement of a low plasma
clozapine concentration (0.19 mg/L). A month after discontinuation of St. John’s
wort, the clozapine concentration was 0.32 mg/L, and after one month thereafter
it was 0.41 mg/L. Also, the psychiatric condition of the patient was improved. 31 As
the author discussed, St. John’s wort may pharmacokinetically interact with clozapine
through inducing CYP3A4, CYP1A2, CYP2C9, and CYP2C19, all of which
are responsible for clozapine metabolism. In addition, P-glycoprotein can also be
induced by this herb. This eventually leads to decreased plasma clozapine levels
and diminished effectiveness. In another case report, Ginkgo biloba can negatively
influence the effect of antiretroviral drug efavirenz (EFV) in an HIV-infected male
patient. This may be due to the induction of G. biloba on CYP2B6 and CYP3A4,
both of which are the drug-metabolizing enzymes for EFV. 32 We can believe that
both the genetic polymorphisms and medicines or herbal products can cause the
variations of enzymes’ activities in individuals.
St. John’s Wort
St. John’s wort is an herb most commonly used for depression and conditions such
as anxiety, tiredness, loss of appetite, and trouble sleeping. There is some strong
evidence that it is effective for mild-to-moderate depression. Currently, there have
been 95 drugs (296 brand and generic names) known to have a major interaction with
St. John’s wort. After administration of St. John’s wort, the AUC 0–∞ of nifedipine
and dehydronifedipine decreased by 42.4% and 20.2% in PXR H1/H2 genotype;
47.9 and 33.0% in H2/H2 genotypes; whereas for the H1/H1 the AUC 0–∞ of nifedipine
decreased 29.0%, but the AUC 0–∞ of dehydronifedipine increased by 106.7%. 33
St. John’s wort treatment significantly increased phenytoin clearance in CYP2C19
extensive metabolizers (EMs) but not in poor metabolizers (PMs) and decreased
the plasma concentrations of omeprazole in a genotype-dependent manner. 34,35
Subjects harboring the ABCB1 haplotype comprising 1236C>T, 2677G>T/A, and
3435C>T polymorphisms had lower intestinal MDR1 mRNA levels and showed an
attenuated inductive response to St. John’s wort as assessed by talinolol disposition. 36
The AUC of voriconazole was decreased by 59% with St. John’s wort treatment, with
a 144% increase in oral clearance of voriconazole. The apparent oral clearance of
voriconazole and the absolute increase in apparent oral clearance were smaller in
CYP2C19*2 carriers than those with CYP2C19*1/*1 genotype. 37