UDP-glucuronosyltransferases and clinical drug-drug interactions

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Abstract

UDP-glucuronosyltransferase (UGT) enzymes catalyze the conjugation of various endogenous substances (e.g., bilirubin) and exogenous compounds (e.g., drugs). The human UGT superfamily is comprised of 2 families (UGT1 and UGT2) and 3 subfamilies (UGT1A, UGT2A, and UGT2B). Many of the individual UGT enzymes are expressed not only in liver but also in extrahepatic tissues, where the extent of glucuronidation can be substantial. Several others (e.g., UGT1A7, UGT1A8, and UGT1A10) are expressed only in extrahepatic tissues. The molecular regulation of UGT enzyme is still not fully understood, but various transcription factors appear to play a regulatory role. The expression of individual UGT enzymes is subject to genetic polymorphism and these enzymes can be inhibited or induced by xenobiotics. Experimental evidence in humans indicates that the glucuronidation of acetaminophen, codeine, zidovudine, carbamazepine, lorazepam, and propafenone can influenced by specific interacting drugs. In contrast, the glucuronidation of diflunisal, morphine, naproxen, and temazepam is not affected appreciably by the drugs investigated to date. In general, UGT-mediated human drug interaction studies are difficult to interpret. The factors that complicate the interpretation of this type of drug interaction data are discussed.

Introduction

Biotransformation is one of the important processes that determine the pharmacokinetic profile of an administered drug. For a drug that undergoes biotransformation, several factors, such as the patient's physiological status, genetic make-up, and coadministered medications, may influence the extent of biotransformation and lead to toxic or subtherapeutic drug concentrations. The area of drug-drug interaction has received notable attention as a result of increased understanding, at the molecular level, of the enzymes responsible for drug biotransformation. In particular, studies have focused on cytochromes P450 and the potential for drug interactions mediated by these enzymes. As a result of the abundant research conducted on this superfamily of enzymes, many reviews on cytochrome P450-mediated drug interactions have been published (e.g., Michalets, 1998, Tanaka, 1998, Dresser et al., 2000). In contrast, other drug-metabolizing enzymes, such as the phase II conjugating enzymes, have received less attention. However, conjugating enzymes are important because many drugs and their metabolites undergo conjugation reactions (Miners et al., 2004). Among the phase II enzymes are the UDP-glucuronosyltransferases (UGTs), which recognize a multitude of functional groups and utilize a common co-substrate, UDP-glucuronic acid, in their conjugating reactions. In fact, UGT-catalyzed glucuronidation reactions are responsible for ∼35% of all drugs metabolized by phase II enzymes (Evans & Relling, 1999). Therefore, it is important to enhance our understanding of the function and regulation of UGT enzymes and the role they play in metabolic drug interactions. The purpose of this review article is to systemically evaluate the scientific literature on inhibition and induction of drug glucuronidation in humans. Only those studies that quantified glucuronide levels will be reviewed. A brief overview on the function, tissue distribution, molecular regulation, pharmacogenetics, inhibition, and induction of UGT enzymes is also provided.

Section snippets

Human UDP-glucuronosyltransferase enzymes

The human UGTs are a superfamily of enzymes that conjugate a variety of endogenous substances and exogenous compounds. Examples of endogenous substrates for UGT include bilirubin, steroid hormones, thyroid hormones, bile acids, and fat-soluble vitamins. Examples of exogenous substrates for UGT include drugs, chemical carcinogens, environmental pollutants, and dietary substances (Ritter, 2000, Tukey & Strassburg, 2000). UGT enzymes are bound to the internal membrane and face the luminal side of

Effect of putative UDP-glucuronosyltransferase inhibitors on drug glucuronidation in humans

This section is mainly a review of prospective, controlled clinical studies on the effect of putative UGT inhibitors on drug glucuronidation. Shown in Table 3 are drug interaction studies that quantified plasma or urinary glucuronide levels. The limitations and the assumptions used in interpreting the glucuronide data are discussed in Section 5.

Effect of putative UDP-glucuronosyltransferase inducers on drug glucuronidation in humans

This section is mainly a review of prospective, controlled clinical studies on the effect of putative UGT inducers on drug glucuronidation. Shown in Table 4 are those studies that quantified plasma or urinary glucuronide levels. The limitations and assumptions used in the interpretation of glucuronide data are discussed in Section 5.

Discussion

The identification and management of drug-drug interactions is an important aspect of patient care. Pharmacokinetic drug interactions may take place at the level of absorption, distribution, metabolism, or excretion. The focus of our review is UGT-mediated drug-drug interactions. A key finding is that UGT-mediated drug interactions can potentially occur for many drugs, as indicated by the various in vitro studies (Table 2). However, the number of clinical studies is considerably less.

Future directions

A review of the available experimental data on drug interaction involving glucuronidation reactions has identified several areas that should be addressed by future studies. It is important to: (1) know the contribution of glucuronidation to the overall biotransformation of a drug because drugs that are extensively glucuronidated are more likely to be affected by UGT enzyme inducers or inhibitors (Lin & Wong, 2002); (2) quantify plasma and urinary levels of the glucuronide in order to assist in

Acknowledgments

This work was supported by the Canadian Institutes of Health Research (grant MOP-42385 to T.K.H.C.). T.K.L.K. received a Masters Award from the Michael Smith Foundation for Health Research.

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