Akademik Veri Yönetim Sistemi
CLINICAL PHARMACOLOGY & THERAPEUTICS, cilt.75, sa.3, ss.191-197, 2004 (SCI-Expanded)
Objective: St John's wort, an extract of the medicinal plant Hypericum perforatum, is widely used as an herbal antidepressant. Although the ability of St John's wort to induce cytochrome P450 (CY-P) 3A4-mediated reaction has been well established, the effect on CYP2C19 is still not determined. Thus the objective of this study was to determine the impact of St John's wort on the pharmacokinetic profiles of omeprazole and its metabolites. Methods. Twelve healthy adult men (6 CYP2C19*1/CYP2C19*1, 4 CYP2C19*21CYP2C19*2 and 2 CYP2C19*2/CYP2C19*3) were enrolled in a 2-phase randomized crossover design. In each phase the volunteers received placebo or a 300-mg St John's wort tablet 3 times daily for 14 days. Then all subjects took a 20-mg omeprazole capsule orally. Blood samples were collected up to 12 hours after omeprazole administration. Omeprazole and its metabolites were quantified by use of HPLC with ultraviolet detection. Results: Omeprazole and its metabolites all exhibit CYP2C19 genotype-dependent pharmacokinetic profiles. After a 14-day treatment with St John's wort, substantial decreases in plasma concentrations of omeprazole were observed. The peak plasma concentration (C-max) significantly decreased by 37.5% 13.3% (P = .001) in CYP2C19*2/CYP2C19*2 or *3 and by 49.6% +/- 20.7% (P = .017) in CYP2C19*/CYP2C19*1; the area under the concentration-time curve extrapolated to infinity [AUC(0-infinity)] decreased by 37.9% +/- 21.3% (P = .014) and 43.9% +/- 23.7% (P = .011) in CYP2C19 mutant and wild genotypes, respectively. Moreover, the C-max and AUC(0-infinity) of omeprazole sulfone increased by 160.3% +/- 45.5% (P = .001) and by 136.6% +/- 84.6% (P = .014), 155.5% +/- 58.8% (P = .001), and 158.7% +/- 101.4% (P = .017) in mutant and wild genotypes, respectively. St John's wort increased the C-max of 5-hydroxyomeprazole by 38.1% +/- 30.5% (P = .028) and the AUC(0-infinity) by 37.2% +/- 26% (P = .005) in CYP2C19 wild-type subjects, whereas it did not produce any significant alterations to the corresponding pharmacokinetic parameters in subjects with variant genotypes. Conclusion: St John's wort induces both CYP3A4-catalyzed sulfoxidation and CYP2C19-dependent hydroxylation of omeprazole and enormously decreases the plasma concentrations of omeprazole. Clinically relevant interactions with other drugs may occur and must be taken into account when St John's wort is being taken.