Quantitative prediction of in vivo inhibitory interactions involving glucuronidated drugs from in vitro data: the effect of fluconazole on zidovudine glucuronidation
Verawan Uchaipichat,Leanne K. Winner,Peter I. Mackenzie,David J. Elliot,J. Andrew Williams,John O. Miners +5 more
TLDR
K(i) values determined under certain experimental conditions may quantitatively predict inhibition of UGT catalysed drug glucuronidation in vivo.Abstract:
Aims
Using the fluconazole–zidovudine (AZT) interaction as a model, to determine whether inhibition of UDP–glucuronosyltransferase (UGT) catalysed drug metabolism in vivo could be predicted quantitatively from in vitro kinetic data generated in the presence and absence bovine serum albumin (BSA).read more
Citations
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Journal ArticleDOI
The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification.
TL;DR: Recent advances in the understanding of the functional roles of UGT, their regulation and tissue expression, and clinical significant factors (ontogeny, interactions and polymorphisms) that affect glucuronidation activity in humans are discussed.
Journal ArticleDOI
Phase II drug metabolizing enzymes
TL;DR: This review covers the major phase II enzymes: UDP-glucuronosyltransferases, sulfotransferases, N-acetyl transferases, glutathione S-transferases and methyltransferases (mainly thiopurine S- methyl transferase and catechol O-methyl transferase) and the focus is on the presence of various forms, on tissue and cellular distribution, on the respective substrates, on genetic polymorphism and finally on the interspecies differences
Journal ArticleDOI
Selectivity of substrate (trifluoperazine) and inhibitor (amitriptyline, androsterone, canrenoic acid, hecogenin, phenylbutazone, quinidine, quinine, and sulfinpyrazone) “probes” for human udp-glucuronosyltransferases
TL;DR: TFP and hecogenin represent selective substrate and inhibitor probes for UGT1A4, although the extensive nonselective binding of the former should be taken into account in kinetic studies.
Journal ArticleDOI
The prediction of drug-glucuronidation parameters in humans: UDP-glucuronosyltransferase enzyme-selective substrate and inhibitor probes for reaction phenotyping and in vitro-in vivo extrapolation of drug clearance and drug-drug interaction potential.
TL;DR: In vitro experimental approaches and scaling strategies have been successfully applied to the quantitative prediction of in vivo clearance via glucuronidation and drug-drug interaction potential.
Journal ArticleDOI
In vitro-in vivo correlation for drugs and other compounds eliminated by glucuronidation in humans: pitfalls and promises.
TL;DR: Intrinsic clearance values generated using human liver microsomes under-predict in vivo hepatic clearance, and in vivo clearances of glucuronidated drugs are generally under-predicted by CL(int) values from human hepatocytes, but to a lesser extent than observed with the microsomal model.
References
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Journal ArticleDOI
Drug-drug interactions for udp-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (auci/auc) ratios
J. Andrew Williams,Ruth Hyland,Barry Jones,Dennis A. Smith,Susan Hurst,Theunis C. Goosen,Vincent Peterkin,Jeffrey R. Koup,Simon E. Ball +8 more
TL;DR: The objective of this article is to encourage those studying ligand interactions with UDP-glucuronosyltransferases (UGTs) to adequately consider the potential consequences of in vitro UGT inhibition in humans, taking the following into account: in vitro data on the enzymology of glucuronide formation from aglycone, pharmacokinetic principles based on empirical data for inhibition of metabolism, and clinical data for drug-drug interactions of drugs primarily cleared by glucuronidation.
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Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance.
Journal Article
Prediction of pharmacokinetic alterations caused by drug-drug interactions: metabolic interaction in the liver.
TL;DR: Serious side-effects caused by drug interactions have attracted a great deal of attention and have become a social problem since the coadministration of ketoconazole and terfenadine was reported to cause potentially life-threatening ventricular arrhythmias.
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Plasma and cerebrospinal fluid pharmacokinetics of 3'-azido-3'-deoxythymidine: a novel pyrimidine analog with potential application for the treatment of patients with AIDS and related diseases.
Raymond W. Klecker,Jerry M. Collins,Robert Yarchoan,Rose V. Thomas,Jean Jenkins,Samuel Broder,Charles E. Myers +6 more
TL;DR: N3TdR possesses pharmacokinetic properties that would facilitate the long‐term treatment of patients with acquired immunodeficiency syndrome: it can be given orally and it penetrates the central nervous system.
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Reversibility by dipyridamole of thallium-201 myocardial scan defects in patients with sarcoidosis.
Philippe Tellier,Frédéric Paycha,Isabelle Antony,Alain Nitenberg,Jean-Marc Foult,Jean-Paul Battesti +5 more
TL;DR: The reversibility of myocardial scan defects is a common finding in sarcoidosis and makes unlikely the role of scar fibrosis or extensive confluent granulomas as a mechanism for such defects.