Effects of Complementary and Alternative Medicines (CAM) on the Metabolism and Transport of Anticancer Drugs

Abstract

The use of complementary and alternative medicines (CAM), such as herbs and dietary supplements, has become more popular among cancer patients. Cancer patients use these supplements for different reasons such as reduction of side effects and improvement of their quality of life. In general, the use of CAM is considered as safe. However, concomitant use of CAM and anticancer drugs could result in serious safety issues since CAM have the potential to cause pharmacokinetic interactions with conventional drugs. Especially for anticancer drugs, pharmacokinetic interactions can easily result in a lower therapeutic efficacy or a higher risk of toxicity due to their small therapeutic windows. Except for St. John’s wort, there is little knowledge about clinical pharmacokinetic interactions between CAM and anticancer drugs. Consequently, for the majority of CAM it is unknown whether concomitant use with anticancer drugs is safe. To address this issue it is crucial to expand the knowledge of the effects of CAM on the metabolism and transport of anticancer drugs. Therefore the aim of this thesis was to determine the in vitro effects of the following frequently used CAM on the metabolism and transport of anticancer drugs: β-carotene, grape seed, Ginkgo biloba, ginseng, green tea, Echinacea, garlic, milk thistle, saw palmetto, St. John’s wort, valerian, vitamin B6, vitamin B12 and vitamin C. Since almost all pharmacokinetic interactions between CAM and anticancer drugs involve cytochrome P450 (CYP) metabolizing enzymes and drug efflux transporters, the in vitro studies focused on the inhibition and induction of these enzymes and transporters by CAM. In summary, milk thistle is the most interesting CAM for clinical follow-up as it was shown to prevent induction of CYP3A4 and to inhibit CYP3A4, CYP2C9, P-gp and BCRP. All these processes possibly result in higher plasma levels of anticancer drugs and consequently in a higher risk of toxicity. Furthermore, the results demonstrated grape seed as potent CYP3A4 inhibitor, green tea as potent CYP3A4 and CYP2C9 inhibitor, St. John’s wort as potent P-gp inhibitor, and Oldenlandia diffusa and St. John’s wort as potent CYP3A4 inducers. Therefore, also grape seed, green tea, St. John’s wort and Oldenlandia diffusa are interesting CAM for clinical follow-up. For clinical studies it is recommended to assess pharmacokinetic interactions between CAM and orally administered anticancer drugs in cancer patients as the effects of CAM on intestinal CYP enzymes and drug efflux transporters is probably more relevant due to the poor bioavailability of CAM.