Can Foods or Herbs Alter the Bioavailability of Chemotherapy Drugs?

Among cancer patients the use of complementary and alternative medicine to treat disease-related depression, alleviate side effects, or even improve therapeutic efficacy varies between 29% in Europe to 87% in the US.^1,2 These medicines comprise supplements, vitamins, minerals and herbs, special foods, and diets as well as massage and spiritual therapy. While vitamins and minerals are the most common complementary and alternative medicines used by cancer patients, herbal supplements rank second. Half of the time, there may be a known risk for a drug interaction, but only around one-third of patients may inform their doctor about the use of these agents.¹ Some can contain pharmacologically active compounds with the potential to alter the bioavailability of cancer drugs by influencing, for example, drug-metabolizing enzymes or transporters.

Interactions arising from concomitant use of bioactive alternatives and conventional chemotherapy could alter plasma levels of active drugs and influence therapeutic efficacy.^3,4 There are a large number of in vitro studies exploring the possible benefits of combining herbal components with anticancer agents, fewer in vivo studies, and very limited clinical data addressing efficacy and safety of combinations. Three illustrative examples include grapefruit juice, St. John’s wort and chrysin. Highlighting these examples provides a viewpoint on the current understanding and underscores pharmacological concepts relevant to a range of combinations currently used by patients or that may arise with new therapeutics.

Grapefruit Juice and Etoposide

Grapefruit juice is probably the most familiar basis of food-drug interactions, arising from well-known influences on oral cholesterol-lowering drugs and selective serotonin reuptake inhibitors on the basis of irreversible inhibition of intestinal cytochrome P450 3A4 (CYP3A4).⁵⁻⁷In vitro microsomal and clinical studies revealed that furanocoumarins, including 6,7-dihydroxybergamottin (Figure 1), are the bioactive constituents in grapefruit juice responsible for intestinal CYP3A4 inhibition.^6,8 The topoisomerase II inhibitor etoposide (Figure 1), a first line treatment for small cell lung cancer, also applied in refractory testicular tumors and leukemia, is also mainly metabolized by CYP3A4, and to a lesser extent CYP1A2 and CYP2E1.^9,10 Thus, inhibition of intestinal CYP3A4 by orally administered grapefruit juice has been hypothesized to result in reduced, presystemic etoposide metabolism.

Figure 1.

Clinically observed pharmacokinetics-based food/herb–drug interactions for grapefruit juice (A) and St. John’s wort (B) in cancer patients and potential interactions for chrysin (C) in anticancer treatment.

On the basis of furanocoumarin inhibition of CYP3A4, and the relevance of this enzyme to etoposide activity, drinking grapefruit juice with etoposide administration may result in increased bioavailability of the orally administered drug. In a randomized crossover study six cancer patients were treated sequentially with etoposide either as intravenous infusion, orally, or orally 15 min after drinking grapefruit juice.¹¹ While the area under the curve (AUC) was highest for intravenous infusion, there was a decrease of 26% in the AUC for orally administered etoposide when it was given after grapefruit juice, suggesting decreased etoposide bioavailability for the combination. This influence might be explained by the inhibition of intestinal uptake transporters after grapefruit juice consumption as demonstrated in cell and other clinical studies, and suggests a relevant impact of a food on chemotherapy drug bioavailability.^6,12

St. John’s Wort and Imatinib, Docetaxel, and Irinotecan

St. John’s wort (SJW) is a perennial plant the extracts of which from the flowering portion have been used over decades in Europe and the US to treat depression, anxiety, and sleeping disorders. In 2002, a population study in the US revealed that 14% of participants took weekly herbal supplements for improving general health with the fourth most common being SJW.¹³ SJW was shown to be a potent inducer of CYP3A4 in human hepatocytes and in healthy volunteers.^14,15 The bioactive compound hyperforin (Figure 1) appears to be responsible for SJW mediated CYP3A4-induction.¹⁶ Like grapefruit juice, but in the opposite direction, there is clinical evidence suggesting that CYP3A4-mediated drug metabolism increased, and therefore bioavailability decreased, after taking high-hyperforin extracts.^17,18

Imatinib (Figure 1) is a specific tyrosine kinase inhibitor used in targeted anticancer therapy of advanced philadelphia chromosome positive leukemia and gastrointestinal stromal tumors.¹⁹ It is mainly metabolized by CYP3A4 to N-desmethylimatinib with a potency similar to imatinib.²⁰ The pharmacokinetic profile of oral imatinib before and after oral long-term administration of SJW extract in healthy volunteers exhibited a decrease in the AUC for imatinib of 30% and an apparent oral clearance increase of 43%.²¹ A similar significant reduction in imatinib bioavailability after long-term intake of SJW was also observed in which the imatinib AUC decreased by 32% after SJW administration.²² These findings indicate the potential for a clinically relevant interaction between SJW and imatinib, and the product information for imatinib by the European Medicines Agency now reflects this. SJW is listed as a substance that may decrease imatinib plasma concentrations significantly and increase the risk of therapy failure, therefore avoiding concomitant use is suggested.²³

A significant decrease in bioavailability after SJW administration was also evident for intravenous docetaxel (Figure 1),²⁴ an anticancer drug widely used for breast, lung, and ovarian carcinomas.²⁵ Docetaxel is a microtubule stabilizer mainly metabolized by CYP3A4 and CYP3A5 to oxidized metabolites with reduced anticancer efficacy observed in cell lines and mice.²⁶ In human hepatocytes, decreased docetaxel plasma concentration after hyperforin exposure at physiological concentrations promoted docetaxel-metabolism.²⁷ In line with this observation, in cancer patients, after oral long-term intake of SJW, the docetaxel AUC decreased by 12%.²⁴ Interestingly, fewer docetaxel-related side effects were observed but the sample size was very small. Thus, while the reduced therapeutic levels associated with SJW suggest a combined use of docetaxel and SJW should be avoided, further studies are anticipated to explore the potential for reducing side effects.

Another anticancer drug with significant clinical SJW interactions is the topoisomerase I inhibitor irinotecan (Figure 1). It is metabolized by CYP3A4 to the more active 7-ethyl-10-hydroxycamptothecin (SN-38);²⁸ therefore, increased CYP3A4 activity could result in undertreatment of patients due to lowered bioavailability of the active drug metabolite. In cancer patients, SJW led to a 42% decrease in SN-38-plasma levels of the intravenously delivered drug.²⁹ This observation suggests possible compromised antitumor activity, however myelosuppression was substantially reduced for the combination, an observation requiring further studies to explore whether this alleviation is only due to lowered bioavailability of the active drug metabolite or if other mechanisms contribute.

A number of examples suggest a real potential for relevant herb–drug interactions generally;^30,31 however, alterations in CYP activity were generally absent after short-term SJW.^15,31 The relevance of herbal therapy regimen dependency for the interaction of SJW with irinotecan could also be demonstrated in experimental animals wherein short-term (3 days) SJW treatment did not alter the pharmacokinetics of irinotecan and SN-38, but long-term (14 days) SJW resulted in 34.2% reduced AUC for SN-38 along with significantly increased clearance.³² In addition, coadministration resulted in less body weight loss, significantly reduced the severity score for early and late onset diarrhea (p < 0.05) and reduced hematological toxicities. The alleviated side effects could be related to drug pharmacokinetics, but in a follow-up study, it was demonstrated that SJW–irinotecan coadministration was accompanied by the reduction of pro-inflammatory cytokines and intestinal epithelium apoptosis, compared to the irinotecan-only treated control.³³ These data illustrate the need for research on herbal active ingredients and their mode of action.

Chrysin and Irinotecan or Docetaxel

Chrysin (Figure 1) is a naturally occurring flavone present in plant extracts from Passiflora caerulea and in honey and is commonly used as an herbal supplement to boost testosterone levels.^34,35 On the basis of observations in intestinal cells, it is hypothesized that taking chrysin supplements may induce the metabolic enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) in the gastrointestinal mucosa.³⁶ This up-regulation could not be confirmed in mice heteterozygous for the human UGT1 locus,³⁷ an observation in line with in vivo data for the topoisomerase I inhibitor irinotecan, which is inactivated by UGT1A1-mediated glucuronidation.²⁸ Oral chrysin cotreatment did not alter the pharmacokinetics of intravenous irinotecan in colorectal cancer patients compared to historical controls.³⁸ However, the low rate of diarrhea observed in this study raised the hypothesis that chrysin may reduce the severity of delayed diarrhea, although this needs to be further investigated. The opposing results for chrysin observed in vitro and in vivo could be based on the low systemic bioavailability of orally administered chrysin, as demonstrated in vitro in caco-2 and Hep2G cells and confirmed in healthy volunteers.^39,40 Most likely, extensive presystemic intestinal and hepatic glucuronidation and sulfation limit possible chrysin interaction to the intestine.³⁹ This offers a potential explanation for the observed reduction in severity of irinotecan-induced diarrhea while plasma levels were not affected by cotreatment with chrysin.

Recently it was shown that chrysin itself suppresses tumor growth of melanoma cells in vitro and in mice.⁴¹ Anticancer activity of chrysin was also demonstrated in breast and lung cell lines and could be confirmed in animal models.³⁴ Underlying mechanisms involve decrease in cell proliferation, induction of apoptosis, and reduction of inflammation.⁴² Also, chrysin has the potential to increase antitumor activity of anticancer drugs and to alleviate side effects.^34,42 Co-exposure of cells to chrysin and docetaxel resulted in increased induction of apoptosis and in a respective xenograft model, the combination was more efficient in delaying tumor growth and reducing the size of tumors.⁴³ In addition, a docetaxel–induced inflammation indicator, paw adema, was reduced by 25% when chrysin was administered orally before intravenous docetaxel treatment. Clinical evidence demonstrating anticancer activity of chrysin is missing and the relevance of these findings needs to be considered critically considering the low systemic bioavailability of chrysin.

Conclusions and Outlook

Herbal supplements are largely used among cancer patients, but clinical evidence for their effects on anticancer drugs is limited. Clinically relevant combinations mainly result in lowered bioavailability of active drug metabolites potentially risking under-treatment in cancer patients.^{11,21,22,24,29} For SJW and docetaxel or irinotecan, in vitro results corresponded with in vivo responses in animals and patients.^24,27,29,32 While this observation certainly cannot be generalized, it provides a case to suggest the potential relevance of addressing in vitro observations of possible compounds that interfere with drug metabolism.⁴⁴ On the other hand, in vitro, chrysin increases UGT1A1 levels, but this induction could not be confirmed in animals and patients presumably due to the low bioavailability of the orally administered herb.^36,38−40 Bioavailability of an herbal active constituent should be carefully evaluated to draw significant conclusions on potential interactions. Chrysin and grapefruit juice drug interactions seemed to be limited to the intestine.^11,38 SJW can also modulate hepatic CYP enzymes and clinically significant interactions for intravenous^24,28 and orally administered drugs.^21,22

While there is extensive pharmacokinetic data for herb-drug interactions, there is limited evidence addressing side effects and mechanisms beyond metabolism.^24,29,38 Reduction of side effects might be explained by reduced drug-bioavailability for herb-drug cotreatment or other mechanisms.^33,43 Furthermore, herbal supplements have chemoprevention activity or are synergistic with conventional drugs while alleviating side effects.^42,45 Thus, there is a need during the development of new drugs and therapeutic strategies for continued attention to potential combination effects. Critical aspects include induction and inhibition of metabolizing enzymes, efflux and influx transporters, detailed knowledge of herbal bioactive ingredients, altered molecular signaling pathways, the translational relevance of possible adverse interactions, and even the possibility for beneficial relationships.

The authors declare no competing financial interest.