ORLANDO, FLA. — St. John's wort converts clopidogrel-resistant patients into responders, Wei C. Lau, M.D., reported at the annual meeting of the American College of Cardiology.
The mechanism by which the herbal product enhances clopidogrel's antiplatelet effect and transforms clopidogrel nonresponders into responders lies in the fact that St. John's wort boosts hepatic cytochrome P450 3A4 metabolic activity. Clopidogrel (Plavix) is activated by this hepatic enzyme. Individuals having inherently low P450 3A4 activity will show clopidogrel resistance. So will patients taking drugs that are cytochrome P450 3A4 inhibitors, explained Dr. Lau, an anesthesiologist at the University of Michigan, Ann Arbor.
He told this newspaper he would recommend using St. John's wort “with discretion” to convert clopidogrel-resistant patients into responders rather than increasing the dosage of the antiplatelet agent to 600 mg/day or more, as some physicians now do in an effort to overcome the resistance despite the expense and increased bleeding risk.
He added that the need for care in using St. John's wort for this purpose stems from the fact that doing so will speed up the metabolism of any other drugs the patient might be taking that are dependent upon the cytochrome P450 3A4 enzyme pathway. One such very widely used drug is atorvastatin. The St. John's wort/atorvastatin interaction would render any given dose of the statin equivalent to a considerably lesser dose.
In an earlier study, he showed that clopidogrel resistance, as defined by relative inhibition of adenosine diphosphate-induced platelet aggregation, is quite common. Indeed, in a group of 57 subjects, of whom 25 were healthy volunteers and 23 had coronary artery disease, 19% were clopidogrel-resistant while another 23% were clopidogrel low-responders. Dr. Lau further showed that clopidogrel's antiplatelet effect correlated inversely with cytochrome P450 3A4 activity (Circulation 2004;109:166–71).
Having previously observed anecdotally that clopidogrel-resistant patients taking St. John's wort seemed to lose their resistance, Dr. Lau and coinvestigators set about in the new study to find the mechanism of benefit. He had six healthy clopidogrel-resistant subjects take 300 mg of St. John's wort three times daily for 2 weeks. Then he measured platelet aggregation by point-of-care whole blood aggregometry prior to a single 450-mg dose of clopidogrel and again 2, 4, and 6 hours later.
The subjects were converted to clopidogrel responders, showing marked enhancement of platelet inhibition at 4 and 6 hours compared with testing done prior to taking St. John's wort. Moreover, erythromycin breath test measurements of hepatic cytochrome P450 3A4 activity performed 4 hours after taking clopidogrel showed a greater than 1.5-fold increase in conjunction with the use of St. John's wort.
St. John's wort is said to boost the metabolic activity of hepatic cytochrome P450 3A4. Lynda Banzi