Mar 6 2005
The widely used herbal remedy St. John's wort appears to amplify the action of the popular blood-thinning drug clopidogrel, sold as Plavix, a small new clinical study finds.
The effect could increase the risk of bleeding among those who take both substances, say the physicians from the University of Michigan Cardiovascular Center who made the finding. But the new finding could also help determine why clopidogrel does not work in some people, and aid the search for new drugs to help them.
The researchers caution that much more clinical study will be needed to confirm the effect. For now, they say, the early finding reinforces how important it is for patients to tell their health care providers about all the herbal remedies they take, as well as their conventional prescription drugs and over-the-counter medications.
"Drugs can interact with drugs, and drugs can interact with herbals, and the result in either case can be dangerous," says lead author Wei C. Lau, M.D., a clinical associate professor of anesthesiology who directs adult cardiac anesthesia at the U-M Health System.
He continues, "We are progressively more aware of previously unknown drug-drug interactions as our knowledge in the field of pharmacogenomics expands. The only safeguard against potential harm is for patients to be completely candid with their doctors about what they're taking, and for physicians to be cognizant of the pharmacological mechanisms of drug metabolism that can help dictate vigilance in asking their patients."
The study, which was presented in a poster at the Annual Scientific Sessions of the American College of Cardiology, involved six healthy people who had been selected for their body's low response to clopidrogrel's blood-thinning properties.
The drug is commonly used to prevent heart attacks and strokes by keeping the platelets in the blood from sticking together. But it is known to be ineffective in some people, and cardiologists often struggle to find another way to thin the blood of so-called clopidogrel low-responders and non-responders who have major cardiovascular risk factors.
Previously, the U-M researchers had found that this individual variation in clopidogrel response stems from variations in the activity of a liver enzyme called CYP3A4.
In 2003, Lau and his colleagues published findings in the journal Circulation, showing that the cholesterol-lowering drug atorvastatin (sold as Lipitor) blocked the action of clopidogrel because it competed for CYP3A4 activity.
Knowing that St. John's wort increased the activity of CYP3A4 in the liver, they decided to look for a possible interaction between the two.
St. John's wort is available in health food stores and drug stores, and marketed as a "natural" antidepressant or mood enhancer. It is known to interact with other drugs, including prescription antidepressants and some antiviral drugs, and to increase the skin's sensitivity to light.
In most cases of interactions known to date, St. John's wort decreases the activity of a medication, rather than increasing it as appears to happen with clopidogrel.
Says Eric Bates, M.D., a professor of cardiovascular medicine who is senior author on the study, "The interesting thing is that by taking this herb, drugs that need to be activated by the CYP3A4 enzyme, such as clopidogrel, perform better. Unfortunately, more drugs are metabolized by this enzyme, so those drugs' activity levels will be lower if this herb is taken. For instance, one would expect that cholesterol lowering with atorvastatin would not be as good when this herb is taken."
The six research participants were selected from a pool of screened volunteers for their low response to 450 milligrams of clopidogrel, as measured using a platelet-aggregation test. First, the participants received only clopidogrel, and platelet aggregation tests to confirm they had less than a 30 percent relative decrease in platelet aggregation.
Then, two weeks later when the drug had entirely left their bodies, they were started on St. John's wort, which they took at a dose of 300 milligrams three times daily for two weeks. After that, they were given 450 mg of clopidogrel again and their platelet activity was monitored for six hours.
All six subjects showed a major decline in platelet aggregation, which was most significant at four hours after clopidogrel was given. From a starting aggregation rate of 90 percent, the average dropped to about 45 percent. The effect was seen using two different tests of platelet aggregation.
Bates notes that the size of the study means the result needs to be confirmed in more people before it has an impact on clinical use of clopidogrel. He and Lau are planning to recruit researchers to launch a larger study later this year. Lau further notes that current studies are underway in a transgenic mouse model to determine the pharmacogenetic mechanism of this observed enhanced effect of clopidogrel by St. John's wort.
In the meantime, Bates echoes Lau's note of warning to patients.
"Too often, people don't realize that the herbal remedies and dietary supplements they take are not regulated and monitored by the U.S. Food and Drug Administration in the same way that prescription drugs and over-the-counter medicines are," he says. "Research on drug-drug and drug-herbal interactions is still in its early stages, but we know that 20 percent or more of Americans regularly take complementary herbs and supplements. The important thing is for doctors and patients to talk openly about this issue, and look for signs of interaction."
In addition to Lau and Bates, the study's authors are David Carville and Kirk Guyer of Indiana University and Charlene Neer of the U-M Department of Anesthesiology.