The effect of St John's Wort on the pharmacodynamic response of clopidogrel in hyporesponsive volunteers and patients: increased platelet inhibition by enhancement of CYP3A4 metabolic activity.

Clopidogrel is metabolically activated by cytochrome P450 (CYP) isoenzymes. We evaluated whether St. John's wort (SJW), a CYP2C19 and CYP3A4 inducer, enhances the pharmacodynamic response of clopidogrel. Volunteers (n = 45) were screened for clopidogrel hyporesponsiveness after a 300-mg load. After a 7-day washout, hyporesponders (n = 10) received 14 days of SJW (300 mg 3 times a day) followed by a second 300-mg clopidogrel. Platelet aggregation was measured at 0, 2, 4, and 6 hours postloading; hepatic CYP3A4 activity was simultaneously determined at 0 and 4 hours by the erythromycin breath test. A prospective, randomized, double-blind pilot study was conducted in postcoronary stent patients (n = 85) on clopidogrel 75 mg/d screened for clopidogrel hyporesponsiveness. Hyporesponders (n = 20) were randomized to SJW (n = 10) or placebo (n = 10); platelet aggregation was measured before and after 14 days of therapy. In volunteers, SJW decreased platelet aggregation (59% ± 14% vs. 40% ± 15% at 2 hours, P = 0.02; 56% ± 10% vs. 44% ± 13% at 4 hours, P < 0.03; and 55% ± 14% vs. 37% ± 14% at 6 hours, P = 0.01) and increased CYP3A4 activity (2.1% ± 0.4% CO2 exhaled per hour before vs. 2.9% ± 0.6% CO2 exhaled per hour after SJW, P = 0.002). In patients, SJW decreased platelet reactivity (226 ± 39 vs. 185 ± 49 P2Y12 reactivity units, P = 0.0002) and increased platelet inhibition (23% ± 11% vs. 41% ± 16%, P = 0.002). SJW may be a future therapeutic option to increase CYP metabolic activity and antiplatelet effect of clopidogrel in hyporesponders.