UDP-glucuronosyltransferases and clinical drug-drug interactions
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.
References (182)
- et al.
Pharmacokinetic drug interaction of morphine, codeine, and their derivatives: theory and clinical reality: Part I
Psychsomatics
(2003) - et al.
Differential regulation of alternate UDP-glucuronosyltransferase 1A6 gene promoters by hepatic nuclear factor-1
Toxicol Appl Pharmacol
(2003) - et al.
Multidrug resistance-associated protein: a protein distinct from P-glycoprotein involved in cytotoxic drug expulsion
Gen Pharmacol
(1997) - et al.
Isolation and characterization of a novel cDNA encoding a human UDP-glucuronosyltransferase active on C19 steroids
J Biol Chem
(1996) - et al.
Isolation and characterization of a human orphan UDP-glucuronosyltransferase, UGT2B11
Biochem Biophys Res Commun
(1998) Inherited disorders of bilirubin metabolism
J Hepatol
(2003)- et al.
Cloning and expression of human UDP-glucuronosyltransferase (UGT) 1A8
Arch Biochem Biophys
(1998) - et al.
Glucuronidation of 7-ethyl-10-hydroxycamptothecin (SN-38) by the human UDP-glucuronosyltransferases encoded at the UGT1 locus
Biochem Biophys Res Commun
(1999) - et al.
The effect of valproic acid on drug and steroid glucuronidation by expressed human UDP-glucuronosyltransferases
Biochem Pharmacol
(2003) - et al.
Loss of analgesic effect of morphine due to coadministration of rifampin
Pain
(1997)
Lack of an effect of valproate concentration on lamotrigine pharmacokinetics in developmentally disabled patients with epilepsy
Epilepsy Res
Glucuronidation of 3′-azido-3′-deoxythymidine in human liver microsomes: enzyme inhibition by drugs and steroid hormones
Biochim Biophys Acta
Drug metabolite kinetics
Pharmacol Ther
Quaternary ammonium-linked glucuronidation of tamoxifen by human liver microsomes and UDP-glucuronosyltransferase 1A4
Biochem Pharmacol
Absence of a pharmacokinetic interaction between chloramphenicol and acetaminophen in children
J Pediatr
The glucuronidation of exogenous and endogenous compounds by stably expressed rat and human UDP-glucuronosyltransferase 1.1
Arch Biochem Biophys
Expression of UDP-glucuronosyltransferases (UGTs) 2B7 and 1A6 in the human brain and identification of 5-hydroxytryptamine as a substrate
Arch Biochem Biophys
Frequent co-occurrence of the TATA box mutation associated with Gilbert's syndrome (UGT1A1*28) with other polymorphisms of the UDP-glucuronosyltransferase-1 locus (UGT1A6*2 and UGT1A7*3) in Caucasians and Egyptians
Biochem Pharmacol
Probenecid and zidovudine metabolism
Lancet
Coma probably induced by lorazepam-valproate interaction
Seizure
Influence of ranitidine on the morphine-3-glucuronide to morphine-6-glucuronide ratio after oral administration of morphine in humans
Human Exp Toxicol
Probencid impairment of acetaminophen and lorazepam clearance: direct inhibition of other glucuronide formation
J Pharmacol Exp Ther
Steady-state dispositions of valproate and diflunisal alone and coadministered to healthy volunteers
Eur J Clin Pharmacol
Effect of naproxen co-administration on valproate disposition
Biopharm Drug Dispos
In vitro interaction of codeine and diclofenac
Drug Metab Dispos
Diclofenac does not interact with codeine metabolism in vivo: a study in healthy volunteers
BMC Clin Pharmacol
Lorazepam-valproate interaction: studies in normal subjects and isolated perfused rat liver
Epilepsia
Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis
Cancer Res
Polymorphisms of UDP-glucuronosyltransferase and pharmacokinetics of irinotecan
Ther Drug Monit
Severe anemia secondary to a probable drug interaction between zidovudine and valproic acid
Clin Infect Dis
The interaction between indomethacin and probenecid. A clinical and pharmacokinetic study
Clin Pharmacol Ther
The effect of propranolol on paracetamol metabolism in man
Br J Clin Pharmacol
The effects of indomethacin and naproxen on zidovudine pharmacokinetics
Br J Clin Pharmacol
The influence of dosage, age and comedication on steady-state plasma lamotrigine concentrations in epileptic children: a prospective study with preliminary assessment of correlations with clinical response
Ther Drug Monit
Lamotrigine plasma concentrations in children and adults: influence of age and associated therapy
Ther Drug Monit
The main role of UGT1A9 in the hepatic metabolism of mycophenolic acid and the effects of naturally occurring variants
Drug Metab Dispos
Activation of the mouse TATA-less and human TATA-containing UDP-glucuronosyltransferase 1A1 promoters by hepatocyte factor 1
Mol Pharmacol
The mechanism of the carbamazepine-valproate interaction in humans
Br J Clin Pharmacol
Genetic polymorphism of UDP-glucuronosyltransferase 2B7 (UGT2B7) at amino acid 268: ethnic diversity of alleles and potential clinical significance
Pharmacogenetics
Paracetamol as a test drug to determine glucuronide formation in man. Effects on inducers and of smoking
Eur J Clin Pharmacol
In vitro characterization of the biotransformation of thiocoraline, a novel marine anti-cancer drug
Invest New Drugs
Comparative N-glucuronidation kinetics of ketotifen and amitriptyline by expressed human UDP-glucuronosyltransferases and liver microsomes
Drug Metab Dispos
Comparative effects of rifampin and/or probenecid on the pharmacokinetics of temazepam and nitrazepam
Int J Clin Pharmacol Ther Toxicol
Effect of propranolol on morphine metabolism
Clin Pharmacol Ther
Genetic variation of human UDP-glucuronosyltransferase: implications in disease and drug glucuronidation
Am J Pharmacogenomics
Pharmacokinetic interaction between rifampin and zidovudine
Antimicrob Agents Chemother
Pharmacogenetic determinants of codeine induction by rifampin: the impact on codeine's respiratory, psychomotor and miotic effects
J Pharmacol Exp Ther
Enhanced cyclophosphamide and ifosafmide activation in primary human hepatocyte cultures: response to cytochrome P-450 inducers and autoinduction by oxazaphosphorine
Cancer Res
Studies on the substrate specificity of human intestinal UDP-glucuronosyltransferases 1A8 and 1A10
Drug Metab Dispos
Human UGT2B7 catalyzes morphine glucuronidation
Drug Metab Dispos
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