Relationship between hyperbilirubinaemia and UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphism in adult HIV-infected Thai patients treated with indinavir

Boyd, Mark; Srasuebkul, Preeyaporn; Ruxrungtham, Kiat; Mackenzie, Peter I.; Uchaipichat, Verawan; Stek, Michael; Lange, Joep M. A.; Phanuphak, Praphan; Cooper, David A.; Udomuksorn, Wandee; Miners, John O.

doi:10.1097/01.fpc.0000197465.14340.d4

Cited by 53 publications

(29 citation statements)

References 25 publications

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“…The potent inhibition of UGT2B10 by several drugs observed in this study is consistent with previous reports from this laboratory, demonstrating that inhibition of other UGT enzymes (e.g., UGT 1A1, 1A9, 2B4, and 2B7) may potentially precipitate DDIs and drugendobiotic interactions (Boyd et al, 2006;Uchaipichat et al, 2006b;Miners et al, 2010b;Raungrut et al, 2010;Pattanawongsa et al, 2015). These observations reinforce the recent recommendations of Regulatory Agencies that new drugs should be evaluated for their potential to inhibit UGT enzymes.…”

Section: Discussionsupporting

confidence: 81%

Human UDP-Glucuronosyltransferase (UGT) 2B10: Validation of Cotinine as a Selective Probe Substrate, Inhibition by UGT Enzyme-Selective Inhibitors and Antidepressant and Antipsychotic Drugs, and Structural Determinants of Enzyme Inhibition

Pattanawongsa

Nair

Rowland

et al. 2015

Drug Metabolism and Disposition

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Although there is evidence for an important role of UGT2B10 in the N-glucuronidation of drugs and other xenobiotics, the inhibitor selectivity of this enzyme is poorly understood. This study sought primarily to characterize the inhibition selectivity of UGT2B10 by UDP-glucuronosyltransferase (UGT) enzyme-selective inhibitors used for reaction phenotyping, and 34 antidepressant and antipsychotic drugs that contain an amine functional group. Initial studies demonstrated that cotinine is a highly selective substrate of human liver microsomal UGT2B10. The kinetics of cotinine N-glucuronidation by recombinant UGT and human liver microsomes (6 bovine serum albumin) were consistent with the involvement of a single enzyme. Of the UGT enzyme-selective inhibitors employed for reaction phenotyping, only the UGT2B4/7 inhibitor fluconazole reduced recombinant UGT2B10 activity to an appreciable extent. The majority of antidepressant and antipsychotic drugs screened for effects on UGT2B10 inhibited enzyme activity with IC 50 values <100 mM. The most potent inhibition was observed with the tricyclic antidepressants amitriptyline and doxepin and the tetracyclic antidepressant mianserin, and the structurally related compounds desloratadine and loratadine. Molecular modeling using a ligand-based approach indicated that hydrophobic and charge interactions are involved in inhibitor binding, whereas spatial features influence the potency of UGT2B10 inhibition. Respective mean K i,u (6 S.D.) values for amitriptyline, doxepin, and mianserin inhibition of human liver microsomal UGT2B10 were 0.61 6 0.05, 0.95 6 0.18, and 0.43 6 0.01 mM. In vitro-in vivo extrapolation indicates that these drugs may perpetrate inhibitory drug-drug interactions when coadministered with compounds that are cleared predominantly by UGT2B10.

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Section: Discussionsupporting

confidence: 81%

Human UDP-Glucuronosyltransferase (UGT) 2B10: Validation of Cotinine as a Selective Probe Substrate, Inhibition by UGT Enzyme-Selective Inhibitors and Antidepressant and Antipsychotic Drugs, and Structural Determinants of Enzyme Inhibition

Pattanawongsa

Nair

Rowland

et al. 2015

Drug Metabolism and Disposition

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“…22 However, the K I reported for fluconazole using zidovudine as a substrate is 529 mM. 22 Consistent with this report, no inhibition was seen below 500 mM with any of the isozymes (Fig. 3G).…”

Section: Resultssupporting

confidence: 79%

“…The antifungal fluconazole (Diflucan, Pfizer, Inc., New York, NY) was included in this screen because it was reported to be a selective inhibitor of UGT2B7. 22 However, the K I reported for fluconazole using zidovudine as a substrate is 529 mM. 22 Consistent with this report, no inhibition was seen below 500 mM with any of the isozymes (Fig.…”

Section: Resultssupporting

confidence: 78%

Automation and Miniaturization of the Bioluminescent UGT-Glo Assay for Screening of UDP-Glucuronosyltransferase Inhibition by Various Compounds

Larson¹,

Kelts

Banks³

et al. 2011

JALA: Journal of the Association for Laboratory Automation

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The uridine 5'-diphospho-glucuronosyltransferase (UGT) family of enzymes is involved in the metabolism of various compounds. These enzymes transfer a hydrophilic glucuronic acid moiety to their substrates, rendering them more water soluble and amenable to excretion. The UGTs act on various endogenous substrates, such as bilirubin, 17β-estradiol, and testosterone, and drugs and other xenobiotics. The function of these enzymes is essential for the clearance of drugs and toxicants, and alteration of UGT activity is a potential cause of adverse drug—drug interactions in vivo. This has stimulated an increased interest in the study of UGT function and inhibition, and the desire to profile new drug entities against UGT enzymes, similar to CYP450 profiling. However, certain factors have hindered the development of a robust method for UGT profiling. Current methods for assessing UGT enzyme activity are laborious and involve protein precipitation and/or chromatographic separation steps, which are not amenable to rapid screening applications for UGT inhibitors or substrates. The approach presented here is a bioluminescent assay for measuring UGT enzyme activity and inhibition in vitro. Using flexible, robust instrumentation in a 384-well microplate format, this study highlights the quick and easy assay implementation for estimation of inhibition kinetics with a variety of known and suspected UGT substrates and inhibitors.

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“…Huang et al (2005) reported that 15% of patients homozygous for the wild-type allele versus 90% of patients homozygous for the UGT1A1*28 allele developed hyperbilirubinemia. Bilirubin plasma levels and the number of cases of jaundice were higher in the group of patients carrying the two mutant alleles (Zucker et al, 2001;Rotger et al, 2005b;Boyd et al, 2006;Rodrí-guez-Nóvoa et al, 2007). Rodríguez -Nóvoa et al (2006) confirmed the relationship between the UGT1A1*28 genotype and the risk of hyperbilirubinemia with atazanavir and indinavir.…”

Section: Pharmacokinetics Of Udp-glucuronosyltransferase and The Riskmentioning

confidence: 99%

The Dual Role of Pharmacogenetics in HIV Treatment: Mutations and Polymorphisms Regulating Antiretroviral Drug Resistance and Disposition

et al. 2012

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Relationship between hyperbilirubinaemia and UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphism in adult HIV-infected Thai patients treated with indinavir

Cited by 53 publications

References 25 publications

Human UDP-Glucuronosyltransferase (UGT) 2B10: Validation of Cotinine as a Selective Probe Substrate, Inhibition by UGT Enzyme-Selective Inhibitors and Antidepressant and Antipsychotic Drugs, and Structural Determinants of Enzyme Inhibition

Human UDP-Glucuronosyltransferase (UGT) 2B10: Validation of Cotinine as a Selective Probe Substrate, Inhibition by UGT Enzyme-Selective Inhibitors and Antidepressant and Antipsychotic Drugs, and Structural Determinants of Enzyme Inhibition

Automation and Miniaturization of the Bioluminescent UGT-Glo Assay for Screening of UDP-Glucuronosyltransferase Inhibition by Various Compounds

The Dual Role of Pharmacogenetics in HIV Treatment: Mutations and Polymorphisms Regulating Antiretroviral Drug Resistance and Disposition

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