ADME properties of herbal medicines in humans: evidence, challenges and strategies.

Herbal medicines, an important group of multicomponent therapeutics, are widely and increasignly used worldwide. Despite the popularitiy of herbal medicines, the clinical evidence that support the use of most herbal medicines is weak. Pharmacokinetic and absorption, distribution, metabolism and excretion (ADME) studies have been integrated into modern drug development, but ADME studies are generally not needed for herbal remedy discovery and development. For the majority of herbal medicines, data on their ADME and pharmacokinetic properties in humans are lacking or scant. An extensive literature search indicates that there are limited data on ADME properties of herbal medicines in humans. Many herbal compounds undergo Phase I and/or Phase II metabolism in vivo, with cytochrome P450s (CYPs) and uridine diphosphate glucuronosyltransferases (UGTs) playing a major role. Some herbal ingredients are substrates of P-glycoprotein (P-gp/MDR1/ABCB1) which is highly expressed in the intestine, liver, brain and kidney. As such, the activities of these drug metabolizing enzymes and drug transporters are critical determining factors for the in vivo ADME processes of herbal remedies. There are increasing ADME studies of herbal remedies, but these studies are mainly focused on a small number of herbal medicines including St John's wort, milk thistle, curcumin, echinacea, ginseng, ginkgo, and ginger. For an herbal medicine, the pharmacological activity is gained when the active agents or the active metabolites reach and sustain proper levels at their sites of action. Both the dose levels and ADME processes of active herbal components in the body govern their target-site concentrations and thus the therapeutic responses. In this regard, a safe and optimal use of herbal medicines requires a full understanding of their ADME profiles. To optimize the use of herbal remedies, further studies to explore their ADME properties in humans are certainly warranted.

Effects of herbal products on the metabolism and transport of anticancer agents.

IMPORTANCE OF THE FIELD: Cancer patients on chemotherapy treatment often seek herbal therapies and this may alter the clearance of anticancer drugs. AREAS COVERED IN THIS REVIEW: Many anticancer drugs are metabolized by CYPs and are substrates of P-glycoprotein, breast cancer resistance protein and multi-drug resistance proteins. CYPs and drug transporters are subject to inhibition and/or induction by the herbal medicines used by cancer patients and the metabolism and pharmacokinetics of anticancer agents may be altered by herbal products. There are increased reports on the interaction of herbal medicines with anticancer agents. A clinical study in cancer patients reported that treatment of St John's wort at 900 mg/day orally for 18 days decreased the plasma levels of the active metabolite of irinotecan, SN-38, by 42%. In healthy subjects, treatment with St John's wort for 2 weeks significantly decreased the systemic exposure of imatinib by 32%. Induction and/or inhibition of CYPs and transporters is considered an important mechanism for these interactions. WHAT THE READER WILL GAIN: Potential interactions of herbal medicines with anticancer agents have become a safety concern in cancer chemotherapy. TAKE HOME MESSAGE: Further studies are warranted to investigate the efficacy and safety profiles of herbal medicines commonly used by cancer patients.

Herbal interactions with anticancer drugs: mechanistic and clinical considerations.

A large number of herbal remedies (e.g. garlic, mistletoe, Essiac, Lingzhi, and astragalus) are used by cancer patients for treating the cancer and/or reducing the toxicities of chemotherapeutic drugs. Some herbal medicines have shown potentially beneficial effects on cancer progression and may ameliorate chemotherapy-induced toxicities. However, there is no or weak scientific basis for the clinical use of these herbal medicines in cancer management and almost none of these plant medicines have been tested in rigorous clinical trials. There are increased reports on the interaction of herbal medicines and anticancer drugs that is becoming a safety concern. For example, a clinical study in cancer patients reported that treatment of St John's wort at 900 mg/day orally for 18 days decreased the plasma levels of the active metabolite of irinotecan, SN-38, by 42%. In healthy subjects, 2 weeks of treatment with St John's wort at 900 mg/day significantly decreased the systemic exposure of imatinib by 32%. In women with advanced breast cancer, coadministration of garlic supplement reduced the clearance of docetaxol by 23.1-35.1%, although the difference did not achieve statistical significance. Most anticancer drugs undergo Phase I and/or II metabolism and are substrates of P-glycoprotein, breast cancer resistance protein, multidrug resistance associated proteins, and/or other transporters. Induction and inhibition of these enzymes and transporters is considered an important mechanism for herb-anticancer drug interactions. Further studies are warranted to investigate potentially harmful herbal interactions with anticancer drugs in patients.