St. John’s Wort May Limit Effectiveness of Chemotherapy

SAN FRANCISCO—St. John’s wort, a popular herbal preparation that is commonly used to treat depression and other illnesses, alters the metabolism of the anticancer agent irinotecan (Camptosar), according to the results of a study presented at the 93rd Annual Meeting of the American Association for Cancer Research (AACR abstract 2443).

Irinotecan, a prodrug of the topoisomerase I inhibitor SN-38, is converted to APC and other inactive compounds via the cytochrome P450 isozyme 3A4 (CYP3A4) pathway. St. John’s wort induces activity of CYP3A4, thus modulating irinotecan metabolism.

"About 50% of all kinds of drugs, including anticancer agents, are metabolized by CYP3A4," said Ron Mathijssen, MD, of the Department of Medical Oncology, Rotterdam Cancer Institute, The Netherlands. "So, the problem is potentially more widespread than this single study shows."

St. John’s wort is available without a prescription in North America and Europe, and sales of this herbal product have increased dramatically over the past decade. According to Dr. Mathijssen, sales of St. John’s wort totaled $6 billion in 1998.

In this randomized crossover trial, five colorectal cancer patients were treated with two courses, 3 weeks apart, of irinotecan given as a 90-minute intravenous infusion at a dose of 350 mg/m². During one course, the patients were treated only with irinotecan; during the other course, they were also given a 21-day regimen of 300 mg of St. John’s wort, taken three times daily and started 14 days before the irinotecan infusion.

Some patients received monotherapy during the first course and cotreatment during the second course and some the reverse order.

Blood samples were taken periodically during the 3 weeks following the infusion, and levels of irinotecan, SN-38, and metabolites of these two compounds were measured by reversed-phase high-performance liquid chromatography with fluo-rescence detection.

Complete pharmacologic data were available from only three of the five patients at the time of the presentation. Expressed as the area under the concentration-time curve (AUC), systemic exposure to SN-38 was reduced by a mean of 50% during cotreatment with St. John’s wort (0.34 µg/h/mL for cotreatment vs 0.70 µg/h/mL for treatment with irinotecan alone). Exposure to the herb increased mean metabolic clearance of APC by 37%.

This study included a very limited number of patients. However, Dr. Mathijssen explained, "we tried to expose a minimum of patients to St. John’s wort. We think it’s unethical to study more patients because of the potential for harm."

Even more troubling, lower levels of SN-38 were observed throughout the study period, indicating that St. John’s wort inhibited the effectiveness of irinotecan for at least 3 weeks after patients stopped taking the herb.

"We conclude that St. John’s wort and irinotecan cannot be given in combination without decreasing the overall antitumor effect of irinotecan. Stopping St. John’s wort treatment only 3 weeks before irinotecan treatment just isn’t good enough," Dr. Mathijssen concluded.

Half Use Alternative Medicines

Speaking at an AACR news briefing, Karen Antman, MD, chief of the division of medical oncology, Columbia University, noted that "about 50% of cancer patients use alternative medicines. Many don’t tell their physicians that they’re taking them."

In addition to potential problems caused by interactions with anticancer drugs, alternative remedies may present other problems. They are not regulated by the FDA and can contain anywhere from "nothing to 10 times what is actually on the label," Dr. Antman said, so physicians have no way of knowing how much of an active substance their patients may be taking. These drugs may also contain contaminants that may interact with anticancer agents and other medications.

Although there is no way to know what exactly is contained within many alternative remedies, both Dr. Mathijssen and Dr. Antman urged physicians to at least know what their patients are taking and try to educate them about possible risks. "I make it a practice to ask, but I’m not sure that my patients all tell me the truth," Dr. Antman said.

Dr. Mathijssen concluded: "We recommend that physicians ask patients if they’re using St. John’s wort or other alternative medicines because patients won’t give this information on their own. Patients don’t realize that it’s a drug because they can buy it in a drugstore without a prescription. Also, patients may think that their doctors won’t take them seriously if they tell them that they use alternative medicine. So it’s very important to ask patients and tell patient why it’s important."