Herb-drug interactions involving drug metabolizing enzymes and transporters

Herbal medicines and their active ingredients are widely used worldwide, and they have become an important part of clinical medicine. The combined use of herbs and drugs has increased the possibility of pharmacokinetic and pharmacodynamic interactions. Clinical studies have demonstrated that the combined use of herbs and drugs can enhance or attenuate the drug efficacy and toxicity. The herb-drug combinations may reduce a drug efficacy and lead to treatment failure when long-term administration. Case reports detailing serious clinical adverse reactions have promoted studies on the interactions between herbs and drugs. This review highlights recent knowledge to discuss herb-drug interactions involving metabolizing enzymes and drug transporters. Drug transporters are widely present in body and play an important role in the absorption, distribution, excretion and metabolism, efficacy, and toxicity of drugs. Investigation of transporters has developed rapidly since 1990s, the effects of many transporters on the pharmacokinetics of drugs and herb-drug interactions have been reported. Some concepts on drug transporters issued experimentally and clinically drug-drug and herb-drug interactions have applied in many studies. Methodology studies are very important for understanding the mechanism, considerations and evaluation of experiments and clinical studies on drug metabolizing enzymes and transporters in drug-drug interactions.     

细胞色素P450酶介导的中药注射剂代谢性相互作用研究现状及思考

中药注射剂因药物相互作用引起的不良反应问题日益凸显,而细胞色素P450（CYP450）酶是影响药物体内处置过程的重要因素,其表达和功能的改变常常引起药动学的变化,是代谢性药物相互作用的主要靶点。因此,开展中药注射剂与化学药的药物相互作用研究十分必要,就CYP450酶介导的中药注射剂与化学药相互作用的研究现状以及常见的中药注射剂对CYP450酶影响的研究进行综述,为中药注射剂的临床应用和相互作用研究提供参考。     

Combination therapy of Western drugs and herbal medicines: recent advances in understanding interactions involving metabolism and efflux

INTRODUCTION: While complementary and alternative medicine markets prosper with an increasing number of consumers of herbal medicines, there is an associated likelihood for herb-drug interactions to occur. Modulation of the activity of metabolic enzymes and/or active transporters by chemical constituents of herbal medicines may influence the therapeutic outcomes of coadministered allopathic medicines due to changes in their pharmacokinetic profiles. Although valuable information on herb-drug interactions is obtained by in vitro studies, such as the mechanisms of interaction, clinical significance of interactions is ultimately demonstrated by in vivo data. AREAS COVERED: The authors outline the mechanisms of herb-drug pharmacokinetic interactions briefly and discuss pharmacokinetic interactions between different therapeutic classes of Western drugs and herbal medicines. Furthermore, the authors also discuss herb-drug interactions from both in vitro and in vivo studies with specific focus on recent findings. EXPERT OPINION: Basic and clinical researches have contributed to the comprehension of the underlying mechanisms involved as well as the practical implications of herb-drug interactions. This provides a foundation for development of guidelines to inform patients about herb-drug interactions that can affect their health.     

Real-world Evidence of the Herb-drug Interactions

Herbal medicine (HM) is a type of medicine that uses active ingredients made from plants to treat diseases and maintain health and wellbeing. Due to its increasing worldwide usage, the possibility of HMs and conventional drugs being concurrently used is high, potentially leading to adverse events resulting from herb-drug interactions. Despite the safety concerns regarding such interactions, few studies have been conducted for assessing clinical consequences of using HMs with conventional drugs in real-world settings. As clinical trials are not forthcoming rapidly enough to provide the evidence for herb-drug interactions, observational studies are considered as an alternative approach. The present review focuses on evaluating the utility of analyzing real-world data in observational research to study the clinical consequences of herb-drug interactions between HMs and conventional drugs. The data sources and study designs of each highlighted literature are examined based on its strengths and limitations in analyzing herb-drug interactions. Finally, future observational studies involving novel and rigorous methodologies that may be effective in studying herb-drug interactions are discussed.     

药物代谢相关基因介导的中草药药物相互作用研究

中草药既是药物也可作为食品补充剂,其应用在国际上越来越广泛。中草药对细胞色素P450酶及其药物转运体的诱导和抑制是介导中草药-药物相互作用和产生药物临床毒副反应的主要机制。中草药能够通过影响药物代谢酶或转运体基因表达和功能改变其底物药物的血药浓度,可能导致临床上药物毒副反应或治疗失败的发生,产生有重要临床意义的中草药-药物相互作用。研究还发现,中草药对药物代谢酶和转运体的影响也受基因剂量控制,即符合基因剂量效应,因而具有遗传的个体差异。本文概述了近年来药物代谢相关基因介导的中草药-药物相互作用及药物基因组学临床研究的最新进展。     

代谢酶和转运体介导的草药-化学药相互作用安全性研究进展

目的 分析药物代谢酶和转运体介导的草药-化学药相互作用(herb-drug interactions,HDIs)和不良反应发生机制,总结常用草药与化学药物之间潜在相互作用的信息.方法 通过PubMed、Web of Science和中国知网等文献检索数据库,对草药、转运体、代谢酶等关键词进行文献检索.结果 草药与化学药...     

Herb-drug interactions: methods to identify potential influence of genetic variations in genes encoding drug metabolizing enzymes and drug transporters

Herbal supplements are often used concomitantly with conventional medications resulting in considerable potential for herb-drug interactions. These interactions, which are generally through interfering with pharmacokinetic and/or pharmacodynamic pathways, may result in beneficial effects or more often adverse reactions such as toxicity or treatment failure and may be influenced by multiple environmental and/or genetic factors. The pharmacogenetic approach may help to identify some interactions which may be more pronounced or only occur in specific groups of subjects although the complex nature of the herbal medicines may limit the discovery of such an interaction. Preclinical studies such as gene expression profiling in rodent liver may help to define metabolic pathways influenced by herbal medicines and facilitate more accurate targeting of human in vivo studies. This review discusses the mechanisms of herb-drugs interaction and the potential influence of genetic variation on herb-drug interactions based on available clinical evidence.     

中西药相互作用的药代动力学机制研究进展

近年来,中西药联合应用日益增多,引起诸多药物相互作用和不良反应。药物代谢酶和转运体在药物的体内代谢和处置过程中发挥重要的作用,中西药联用不仅会改变药物的理化性质和人体的生理特性,而且可以调节药物代谢酶和转运体的表达和功能,进而产生药动学相互作用,引起药物疗效的改变。本文对中西药相互作用的药动学基础及其评价方法进行总结,旨在为中西药的联合应用和研究提供参考。     

Potential of pharmacokinetic profiling for detecting herbal interactions with drugs

The issue of herb-drug interactions has generated significant concern within the pharmaceutical industry and among regulatory authorities in recent years. Therefore, accurate models of predicting metabolic herb-drug interactions would be useful tools in efforts to avoid toxic adverse events. However, the majority of pharmacokinetic interactions listed for herbal medicinal products are based on theoretical predictions of the in vitro pharmacological effects of known constituents, which do not necessarily have to be the active ingredients. The prediction of herb-drug interactions is further complicated by the fact that pharmacokinetic data on active or (at least) known ingredients are often not available. The present article discusses the potential of pharmacokinetic profiling for detecting herb-drug interactions, using the most frequently cited interactions in the literature as examples. In particular, common mechanisms of herb-drug interactions are summarized, and the available experimental methods for detecting such interactions, as well as the limitations of these models, are critically evaluated. In addition, we discuss the question of whether the existing methods of detecting herb-drug interactions correlate with the clinical relevance. Effective screening tools that accurately predict metabolic herb-drug interactions would offer a tremendous advantage because it is not possible to study all potential herb-drug interactions in clinical trials.     

Herb-drug interactions and mechanistic and clinical considerations

Herbal medicines are often used in combination with conventional drugs, and this may give rise to the potential of harmful herb-drug interactions. This paper updates our knowledge on clinical herb-drug interactions with an emphasis of the mechanistic and clinical consideration. In silico, in vitro, animal and human studies are often used to predict and/or identify drug interactions with herbal remedies. To date, a number of clinically important herb-drug interactions have been reported, but many of them are from case reports and limited clinical observations. Common herbal medicines that interact with drugs include St John's wort (Hypericum perforatum), ginkgo (Ginkgo biloba), ginger (Zingiber officinale), ginseng (Panax ginseng), and garlic (Allium sativum). For example, St John's wort significantly reduced the area under the plasma concentration-time curve (AUC) and blood concentrations of cyclosporine, midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline. The common drugs that interact with herbal medicines include warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus and irinotecan. Herbal medicines may interact with drugs at the intestine, liver, kidneys, and targets of action. Importantly, many of these drugs have very narrow therapeutic indices. Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). The underlying mechanisms for most reported herb-drug interactions are not fully understood, and pharmacokinetic and/or pharmacodynamic mechanisms are implicated in many of these interactions. In particular, enzyme induction and inhibition may play an important role in the occurrence of some herbdrug interactions. Because herb-drug interactions can significantly affect circulating levels of drug and, hence, alter the clinical outcome, the identification of herb-drug interactions has important implications.     

Clinical risk management of herb-drug interactions

The concomitant use of conventional and herbal medicines can lead to clinically relevant herb-drug interactions. Clinical risk management offers a systematic approach to minimize the untoward consequences of these interactions by paying attention to: (i) risk identification and assessment; (ii) development and execution of risk reduction strategies; and (iii) evaluation of risk reduction strategies. This paper reviews which steps should be explored or taken in these domains to improve the clinical risk management of adverse herb-drug interactions.     

Clinical-pharmacological strategies to assess drug interaction potential during drug development.

Drug interactions in patients receiving multiple drug regimens are a constant concern for the clinician. With the increased availability of new drugs and their concomitant use with other drugs, there has been a rise in the potential for adverse drug interactions as demonstrated by the recent withdrawals of newly marketed drugs because of unacceptable interaction profiles. Therefore, the interaction potential of a new compound has to be assessed in detail, starting with preclinical in vitro and in vivo studies at candidate selection and continuously followed up through preclinical and clinical development. Since formal in vivo studies of all possible drug interactions are neither practicable nor suggestive, a careful selection of a limited number of drug combinations to be investigated in vivo during the development phase is indicated. Based on knowledge of pharmacokinetic and biopharmaceutical properties, a well balanced link between in vitro investigations and carefully selected in vivo interaction studies allows full assessment of the potential of a new drug to cause clinically relevant pharmacokinetic drug-drug interactions, prediction of a lack of interactions and derivation of the proper dose recommendations. Clinical pharmacology plays a number of key roles within the process of collecting information on drug interactions during preclinical and clinical development: addressing issues and/or favourable properties to be expected, thus contributing to the scientific assessment of development potential; setting up a rational in vivo drug-drug interaction programme; performing early mechanistic studies to link in vitro with in vivo information (employing 'cocktail' approaches if possible); reviewing co-medication sections for clinical trials; and conducting labelling-oriented interaction studies, after proof of concept. The fact that interactions can occur between various active substances should by itself be a conclusive argument against unnecessary polypharmacy. Prescribing fewer drugs on a rational basis can reduce the risk of adverse effects secondary to drug interactions and may help to improve the quality of drug treatment and to save costs.     

A guide for assessing pharmacoepidemiologic studies.

Pharmacoepidemiologic studies are appearing with increasing frequency in clinical journals, describing associations between commonly used drugs and rare adverse clinical events. Before practitioners accept conclusions of causality and alter patterns of practice based on these studies, they should perform two steps: apply a critical appraisal filter to the evidence to determine whether the claims are justified, and explore the consequences of not using a drug associated with an undesired effect. This guide for critically appraising the literature on adverse drug effects emphasizes the need to evaluate the potential biases associated with studies that use nonexperimental designs.     

Evaluation of metabolism-mediated herb-drug interactions

As the use of herbal medicines increases, the public health consequences of drug-herb interactions are becoming more significant. Herbal medicines share the same drug metabolizing enzymes and drug transporters, including cytochrome P450 enzymes (CYPs), glucuronosyltransferases (UGTs), and P-glycoprotein, with several clinically important drugs. Interactions of several commonly used herbal medicines, such as Ginko biloba, milk thistle, and St. John’s wort, with therapeutic drugs including warfarin, midazolam, alprazolam, indinavir, saquinavir, digoxin, nifedipine, cyclosporine, tacrolimus, irinotecan, and imatinib in humans have been reported. Many of these drugs have very narrow therapeutic indices. As the herb-drug interactions can significantly alter pharmacokinetic and pharmacodynamic properties of administered drugs, the drugs interacting with herbal medicines should be identified by appropriate in vitro and in vivo methods. A good understanding of the mechanisms of herb-drug interactions is also essential for assessing and minimizing clinical risks. In vitro methods are useful for providing mechanistic information and evaluating multiple components in herbal medicines. This review describes major factors affecting the metabolism of herbal medicines, mechanisms of herb-drug interactions mediated by CYPs and UGTs, and several in vitro methods to assess the herb-drug interactions. Finally, drug interactions of Ginkgo biloba and St. John’s wort, as representative herbal medicines, are described.     

Predicting pharmacokinetic herb-drug interactions

In vitro and in vivo studies have indicated that the induction or inhibition of cytochrome P450 (CYP) is one of the major mechanisms for some clinically important pharmacokinetic herb-drug interactions. Thus, an attempt was made to predict pharmacokinetic herb-drug interactions using the pharmacokinetic principles that are used for predicting drug-drug interactions. The expected AUC ratio was mainly dependent on unbound herbal inhibitor concentration ([I]) and inhibition constant (Ki), hepatic fraction (fh), number of inhibitory herbal constituents (n) and metabolic pathway fraction in hepatic metabolism (fm). Herb-drug interactions would be with low risk if sigma(i=1)n [[Ii]/Ki(i)] is less than 0.1, medium risk if it is between 0.1 and 1.0, and high risk if it is greater than 1. For high clearance drugs, the change of fh x fm had minor influence on AUC ratio when sigma(i=1)n [[Ii]/Ki(i)] values were fixed. Similarly, fm did not affect the AUC ratio for low clearance drugs. It appeared likely to predict a herb-drug metabolic interaction when [I], Ki, fh, fm and n could be determined. However, many herb- and drug-related factors may cause difficulties with the prediction, and well-designed human studies are always necessary.