Enzyme Kinetics of Uridine Diphosphate Glucuronosyltransferases (UGTs)

Jin Zhou, Upendra A. Argikar, John O. Miners

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

7 Citations (Scopus)


Glucuronidation, catalyzed by uridine diphosphate glucuronosyltransferases (UGTs), is an important process for the metabolism and clearance of many lipophilic chemicals, including drugs, environmental chemicals, and endogenous compounds. Glucuronidation is a bisubstrate reaction that requires the aglycone and the cofactor, UDP-GlcUA. Accumulating evidence suggests that the bisubstrate reaction follows a compulsory-order ternary mechanism. To simplify the kinetic modeling of glucuronidation reactions in vitro, UDP-GlcUA is usually added to incubations in large excess. Many factors have been shown to influence UGT activity and kinetics in vitro, and these must be accounted for during experimental design and data interpretation. While the assessment of drug–drug interactions resulting from UGT inhibition has been challenging in the past, the increasing availability of UGT enzyme-selective substrate and inhibitor “probes” provides the prospect for more reliable reaction phenotyping and assessment of drug–drug interaction potential. Although extrapolation of the in vitro intrinsic clearance of a glucuronidated drug often underpredicts in vivo clearance, careful selection of in vitro experimental conditions and inclusion of extrahepatic glucuronidation may improve the predictivity of in vitro–in vivo extrapolation. Physiologically based pharmacokinetic (PBPK) modeling has also shown to be of value for predicting PK of drugs eliminated by glucuronidation.

Original languageEnglish
Title of host publicationEnzyme Kinetics in Drug Metabolism
Subtitle of host publicationFundamentals and Applications
EditorsSwati Nagar, Upendra A. Argikar, Donald Tweedie
Place of PublicationNew York
PublisherHumana Press Inc.
Number of pages38
ISBN (Electronic)9781071615546
ISBN (Print)9781071615539
Publication statusPublished - 2021

Publication series

NameMethods in Molecular Biology
ISSN (Print)1064-3745
ISSN (Electronic)1940-6029


  • Albumin effect
  • Atypical kinetics
  • Bisubstrate kinetics
  • Drug–drug interactions
  • Enzyme kinetics
  • Glucuronidation
  • Human liver microsomes
  • In vitro–in vivo extrapolation
  • Latency
  • PBPK—physiologically based pharmacokinetic modeling
  • Protein–protein interactions
  • Reaction phenotyping
  • Relative activity factor
  • UDP-glucuronic acid
  • UDP-glucuronosyltransferase
  • β-Glucuronidase


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