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

Wei C. Lau, Terrence D. Welch, Theresa Shields, Melvyn Rubenfire, Udaya S. Tantry, Paul A. Gurbel

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)86-93
Number of pages8
JournalJournal of Cardiovascular Pharmacology
Volume57
Issue number1
DOIs
StatePublished - Jan 2011

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clopidogrel
Hypericum
Cytochrome P-450 CYP3A
Volunteers
Blood Platelets
Platelet Aggregation
Cytochrome P-450 Enzyme System
Breath Tests
Erythromycin
Double-Blind Method
Isoenzymes
Stents

Keywords

  • aggregation
  • Cardiovascular pharmacology
  • clopidogrel
  • platelet function inhibitors
  • platelets

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

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. / Lau, Wei C.; Welch, Terrence D.; Shields, Theresa; Rubenfire, Melvyn; Tantry, Udaya S.; Gurbel, Paul A.

In: Journal of Cardiovascular Pharmacology, Vol. 57, No. 1, 01.2011, p. 86-93.

Research output: Contribution to journalArticle

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abstract = "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.",
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