Clinical Pharmacokinetic Interactions between Herbal Supplements and Anticancer Drugs

Abstract

In cancer treatment the response to chemotherapy is often characterized by a wide interpatient variability. The increasing popularity of herbal supplements among cancer patients may contribute to this phenomenon. Since these supplements may affect drug metabolizing cytochrome P450 (CYP) enzymes, plasma concentrations of anticancer drugs could alter due to pharmacokinetic herb-drug interactions. Consequently, patients could be undertreated or have an increased risk of toxicities. To prevent these serious consequences, it is of interest to identify potential pharmacokinetic herb-drug interactions in cancer patients. However, clinical studies concerning pharmacokinetic interactions between herbal supplements and anticancer drugs are relatively scarce. Therefore, the main objective of this thesis was to investigate pharmacokinetic interactions between widely used herbal supplements and anticancer drugs in cancer patients. All investigated herbal supplements showed significant effects on CYP enzymes in vitro. One of our clinical studies showed that Echinacea purpurea (Echinaforce®) at the recommended dose did not significantly alter the pharmacokinetics of docetaxel and therefore this herb-drug combination can be considered safe. Most likely, this result also applies to other batches of Echinaforce®, since the interbatch variation in alkylamide content was relatively small in a quality control analysis of multiple Echinaforce® liquid extracts. In another clinical study St. John’s wort (Hyperiplant®) at the recommended dose significantly decreased the plasma levels of docetaxel in cancer patients. Based on this result cancer patients are advised to refrain from St. John’s wort during chemotherapy with docetaxel in order to prevent potential undertreatment. The clinical effects of grape seed extract on the activity of CYP2D6, which is an essential enzyme in the biotransformation of tamoxifen, was investigated in healthy volunteers. In this study the sensitive CYP2D6 substrate dextromethorphan served as a model drug for tamoxifen. Supplementation with grape seed extract did not significantly affect the urinary metabolic ratio of dextromethorphan. Thus, grape seed extract appears to be safe to combine with dextromethorphan and drugs extensively metabolized by CYP2D6. In an ongoing study the potential inhibiting effects of milk thistle on the pharmacokinetics of docetaxel and tolbutamide are investigated in cancer patients. In this study tolbutamide and docetaxel served as substrates of CYP2C9 and CYP3A4, respectively. Preliminary results showed that the pharmacokinetics of tolbutamide and docetaxel were not substantially affected by milk thistle supplementation. However, definitive conclusions of this study cannot be drawn prior to evaluation of the last patient. In summary, St. John’s wort significantly decreased the systemic exposure of docetaxel, suggesting that this herb-drug combination should be avoided. In contrast, the investigated commercial products of Echinacea purpurea and grape seed extract may be considered safe to combine with CYP3A4 and CYP2D6 substrates, respectively. This thesis shows that significant effects of herbal supplements on CYP enzymes in vitro are often not extrapolatable to humans. Therefore, clinical studies should be performed to confirm significant results obtained in vitro. Considering the results of the clinical studies described in this thesis, the majority of the herbal supplements, except St. John’s wort, seems to pose limited risk for causing pharmacokinetic interactions with anticancer drugs.