Identification of drugs that interact with herbs in drug development

doi:10.1016/j.drudis.2007.06.004

Drug Discovery Today

Volume 12, Issues 15–16, August 2007, Pages 664-673

https://doi.org/10.1016/j.drudis.2007.06.004 Get rights and content

To date, several clinically important drugs have been identified that interact with commonly used herbs. These drugs include (among others) warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus and irinotecan. 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). Because drug–herb interactions can significantly affect circulating levels of drug and, hence, alter the clinical outcome, the identification of drugs that interact with commonly used herbal medicines has important implications in drug development. In silico, in vitro, animal and human studies are often used to identify drug interactions with herbs. We propose that drug–herb and herb–CYP interaction studies should be incorporated into drug development.

Introduction

Herbal medicines are becoming popular worldwide, despite their mechanisms of action being generally unknown, the lack of evidence of efficacy, and inadequate toxicological data. An estimated one third of adults in developed nations and more than 80% of the population in many developing countries use herbal medicines in the hope of promoting health and to manage common maladies such as colds, inflammation, heart disease, diabetes and central nervous system diseases. To date, there are more than 11 000 species of herbal plants that are in use medicinally and, of these, about 500 species are commonly used in Asian and other countries. These herbs are often co-administered with therapeutic drugs raising the potential of drug–herb interactions, which may have important clinical significance based on an increasing number of clinical reports of such interactions.

The interaction of drugs with herbal medicines is a significant safety concern, especially for drugs with narrow therapeutic indices (e.g. warfarin and digoxin). Because the pharmacokinetics and/or pharmacodynamics of the drug may be altered by combination with herbal remedies, potentially severe and perhaps even life-threatening adverse reactions may occur. Because of the clinical significance of drug interactions with herbs, it is important to identify drugs and compounds in development that may interact with herbal medicines. Timely identification of such drugs using proper in vitro and in vivo approaches may have important implications for drug development.

Section snippets

Drugs that interact with herbal medicines in humans

Literature searches were performed using the following databases: Medline (via Pubmed), Biological Abstracts, Cochrane Library, and Embase (all from their inception to March 2007). All human in vivo studies relating to drug–herb interactions were included, whereas data from animal and in vitro drug interaction studies were generally excluded, except for those exploring mechanisms for drug–herb interactions. Only articles in English were included. Human studies included case reports, case

Mechanisms for drug interactions with herbal medicines

The underlying mechanisms for most reported drug interactions with herbal medicines have not been fully elucidated. As with drug–drug interactions, both pharmacokinetic and pharmacodynamic mechanisms are implicated in these interactions (Figure 1). Alterations in absorption, metabolism, distribution or excretion of drugs are the cause of pharmacokinetic interactions. Altered drug metabolism by herbal medicines is often a result of CYP induction and/or inhibition [17]. The most well studied and

Clinical significance of identification of drugs that may interact with herbs

When a drug's clearance is significantly altered, or its drug targets are the same as the herbal components, a clinically important drug interaction with herbs may occur (Figure 2). Herbal medicines that are able to modulate intestinal and hepatic CYPs and P-gp often alter the bioavailability and clearance of co-administered drugs [1]. Many commonly used herbal medicines have been shown to alter the plasma clearance of therapeutic drugs. For example, long-term treatment of St John's wort

Approaches to identifying drugs that may interact with herbal medicines

To avoid or minimize toxic drug–herb interactions, it is important to identify drugs that can interact with herbs using proper in vitro and in vivo models in the early stages of drug development (Figure 3). Such models have very different cost, reliability and possibility for high throughput studies. Thus, these models may be used in combination to obtain enough information that is useful for providing warning and proper advice to patients in clinical practice.

There is an increasing use of in

Predicting a drug's potential for interaction with herbal medicines

It should be possible to predict drug–drug interactions, assuming proper principles are followed. However, unlike the prediction of metabolic drug–drug interactions where there have been several successes with those drugs mainly metabolized by CYPs [58], the prediction of drug interactions with herbs appears to be more problematic. Prediction is hampered by the following factors associated with the drug, herb and/or patients: (a) herb medicines often contain more than 100 constituents with

Implications of identification of drugs that may interact with herbs in drug development

Interactions of drugs with herbal supplements are difficult to anticipate because of the general lack of information characterizing their pharmacologic actions and composition. The dramatic rise in the use of herbal medicine worldwide means that many more patients on conventional medicines are being exposed to herbal medicines. Thus, timely identification of drugs capable of interacting with herbs is important to remind drug scientists of the possible safety concerns arising from combined use

Conclusions and future perspectives

A major safety concern is the potential for interactions of herbal products with prescribed drugs. This issue is especially important with respect to drugs with narrow therapeutic indices (e.g. warfarin and digoxin) [65]. This may lead to adverse reactions that are sometimes life threatening or lethal [40]. The identification of drugs that interact with herbs has important implications in drug development. It appears that any new drugs that are substrates for CYP3A4 and/or P-gp have the

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ReviewPost ScreenIdentification of drugs that interact with herbs in drug development

Introduction

Section snippets

Drugs that interact with herbal medicines in humans

Mechanisms for drug interactions with herbal medicines

Clinical significance of identification of drugs that may interact with herbs

Approaches to identifying drugs that may interact with herbal medicines

Predicting a drug's potential for interaction with herbal medicines

Implications of identification of drugs that may interact with herbs in drug development

Conclusions and future perspectives

Am. J. Transplant

J. Heart Lung Transplant

Lancet

Pharmacol. Ther.

Cell

Int. J. Biochem. Cell Biol.

Chem-Biol. Interact.

Adv. Drug Deliver. Rev.

J. Ethnopharmacol.

Am. J. Gastroenterol.

Curr. Ther. Res.

Lancet

J. Pharmacol. Toxicol. Method

Life Sci.

Lancet

Lancet

J. Hepatol.

Therapie

Lancet

J. Chromatogr. Biomed. Appl

Contraception

Herb–drug interactions: a literature review

Drugs

Effects of St. John's wort supplementation on ibuprofen pharmacokinetics

Ann. Pharmacother.

Pharmacodynamic interaction studies of Ginkgo biloba with cilostazol and clopidogrel in healthy human subjects

Br. J. Clin. Pharmacol.

Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance

Clin. Pharmacol. Ther.

Pharmacokinetic interaction between levofloxacin and ciclosporin or tacrolimus in kidney transplant recipients: ciclosporin, tacrolimus and levofloxacin in renal transplantation

Clin. Pharmacokinet.

Effects of ezetimibe on cyclosporine pharmacokinetics in healthy subjects

J. Clin. Pharmacol.

Pharmacotherapy: A Pathophysiologic Approach

The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions

J. Clin. Invest

Regulation of CYP3A gene transcription by the pregnane X receptor

Annu. Rev. Pharmacol. Toxicol.

International Union of Pharmacology. LXII. The NR1H and NR1I receptors: constitutive androstane receptor, pregnene X receptor, farnesoid X receptor alpha, farnesoid X receptor beta, liver X receptor alpha, liver X receptor beta, and vitamin D receptor

Pharmacol. Rev.

PXR and CAR: nuclear receptors which play a pivotal role in drug disposition and chemical toxicity

Drug Metab Rev.

Summary of information on human CYP enzymes: Human P450 metabolism data

Drug Metab Rev.

Herbal modulation of P-glycoprotein

Drug Metab Rev.

The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux

Nat Med.

Carbamazepine is not a substrate for P-glycoprotein

Br. J. Clin. Pharmacol.

St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor

Proc. Natl. Acad. Sci. U. S. A.

Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor

Mol. Pharmacol.

St John's wort, a herbal antidepressant, activates the steroid X receptor

J. Endocrinol.

St John's Wort: effect on CYP3A4 activity

Clin. Pharmacol. Ther.

St John's wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4

Clin. Pharmacol. Ther.

St John's Wort increases expression of P-glycoprotein: implications for drug interactions

Br. J. Clin. Pharmacol.

Saint John's wort: an in vitro analysis of P-glycoprotein induction due to extended exposure

Br. J. Pharmacol.

Coordinate induction of both cytochrome P4503A and MDR1 by St John's wort in healthy subjects

Clin. Pharmacol. Ther.

Pharmacokinetic interactions of drugs with St John's wort

J. Psychopharmacol.

Impact of ginkgo biloba on the pharmacokinetics of digoxin

Am. J. Ther.

Review
Post Screen
Identification of drugs that interact with herbs in drug development