St John’s Wort interferes with chemotherapy, study shows

BMJ web report

Cancer patients who take the herbal remedy St John’s Wort (Hypericum perforatum) may jeopardise their response to chemotherapy, according to a small study that examined the effect of the herb on the metabolism of the antineoplastic agent irinotecan (Journal of the National Cancer Institute 2002;94:1247-9).

St John’s Wort is known to induce the cytochrome P450 hepatic enzyme system. Specifically, the herb induces the expression of an isoform of the P450 enzyme system known as CYP3A4. This enzymatic cascade is heavily used by the body to break down a variety of drugs and toxins.

More than half of the chemotherapeutic agents now used are broken down by the cytochrome system. Among antineoplastic agents metabolised through the liver in the P450 system are the vinca alkaloids and the drugs etoposide, teniposide, anthracycline, paclitaxel, docetaxel, and tamoxifen.

Because many cancer patients seek alternative treatments and herbal remedies, Dr Ron Mathijssen, Dr Alex Sparreboom, and colleagues from the Department of Medical Oncology at the Erasmus University Daniel den Hoed Cancer Centre, Rotterdam, sought to determine whether a significant drug interaction occurred between St John’s Wort and irinotecan, an antineoplastic agent used against colon cancer.

Normally irinotecan is metabolised by the liver into its active metabolite, SN-38, which is responsible for irinotecan’s chemotherapeutic effect. Interference with irinotecan’s metabolism through overactivation of the CYP3A4 pathway could affect the bioavailabilty and potency of its active ingredient.

In a non-blinded, randomised crossover study, five cancer patients were treated with irinotecan (350 mg/mg2 intravenously), with or without St John’s Wort (300 mg three times a day orally), for 18 days. The patients started taking St John’s wort two weeks before their first or second infusion of irinotecan and continued taking it daily until four days after the last dose of irinotecan.

The researchers found that the plasma concentrations of SN-38 decreased by 42% (95% confidence interval 14% to 70%, P=0.33), when measured by the area under the plasma concentration-time curve, in patients who took St John’s wort. Also, bone marrow suppression was reduced in the presence of St John’s wort.

Commenting on their study, Dr Sparreboom said that the results indicated that the increased metabolism could render the chemotherapy useless.

He added: “It is not known for how long patients should stop taking St John’s wort before receiving their chemotherapy drugs. Our trial suggests that the negative effects of St John’s wort on irinotecan therapy are still observable even three weeks after the last dose of St John’s wort. Thus, physicians should consider the possibility of very prolonged – more than three weeks – and durable effects.”

While the study was small, it is considered important because most antineoplastic drugs use the cytochrome P-450 system, and St John’s wort was previously shown to interfere with the effectiveness of antiretroviral protease inhibitors through a similar mechanism.

In an accompanying editorial, Dr Patrick Mansky and Dr Stephen Straus of the US National Institute of Health’s Center for Complementary and Alternative Medicine, said that among the herbal remedies reports of drug interactions with St John’s wort had been “the most impressive.” Meanwhile, the centre is actively funding more studies to investigate the effectiveness and interactions of herbal medicines.

Nebraska DJ. BMJ 2002;325:460 ( 31 August )

Mathijssen RH, Verweij J, de Bruijn P et al. Effects of St. John’s wort on irinotecan metabolism. J Natl Cancer Inst 2002 Aug 21;94(16):1247-9

J Natl Cancer Inst. 2002 Aug 21;94(16):1187-8.

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