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In Vitro UDP-glucuronosyltransferase (UGT) Enzyme Inhibition Studies

For drug candidates that are cleared predominantly by UDP-glucuronosyltransferase (UGT) conjugation, UGT inhibition studies may be recommended by regulatory agencies prior to submission as part of the drug candidate’s preclinical development program.

Glucuronidation is a major pathway of xenobiotic biotransformation in mammalian species, and the reaction is catalyzed by UDP-glucuronosyltransferases (UGTs), which are located primarily in the endoplasmic reticulum of liver cells. Since drug-drug interactions (DDIs) that are at least partly due to inhibition of UGTs have been reported, identification of the UGT(s) involved in the metabolism of a compound can allow for a better DDI prediction.

Our Approach to UGT Inhibition Studies for Preclinical Drug Development

Our study design evaluates drug candidates as direct-acting inhibitors of UGT enzymes in human liver microsomes and features low protein concentrations and short incubation times to minimize artifacts caused by protein binding, metabolic instability of the test article, and excessive metabolism of the marker substrate.

Enzymes play an important part in drug metabolism

Features of UGT Enzyme Inhibition Analysis & Evaluation

  • Validated LC-MS/MS methods
  • Deuterated internal standards in most cases
  • Positive control inhibitor for all UGTs
  • Designed to minimize UGT inhibitor depletion
  • Pooled, extensively-characterized, glycerol-free1 human liver microsomes
  • Comprehensive report

Assay Selection

UGT ENZYME
UGT1A1 17β-Estradiol 3-glucuronidation
UGT1A3 Chenodeoxycholic acid 24-O-glucuronidation
UGT1A4 Trifluoperazine glucuronidation
UGT1A6 1-Naphthol glucuronidation
UGT1A9 Propofol glucuronidation
UGT2B7 Morphine 3-glucuronidation
UGT2B15 S-Oxazepam glucuronidation
UGT2B17 Testosterone 17β-O-glucuronidation

Test System

UGT Inhibition assays are typically performed with pooled human liver microsomes from 200 donors (XTreme 200). This allows similar experimental conditions to be used to study all UGT enzymes of interest.

Incubation Conditions

Protein concentration: ≤ 0.1 mg/mL
Incubation time: 5-10 minutes

Results

Direct inhibition IC50 values determined from seven concentrations of the drug candidate.

Inhibition Follow-up Service Offerings

KI determinations

Determine KI value and mechanism associated with direct inhibition with multiple concentrations of the drug candidate and marker substrate.

Related Service: Inhibition Screening

Discovery Plus™ Screening Suite presents medium-throughput alternatives to definitive metabolism & DDI studies through non-GLP, condensed versions of our definitive assays. This option is best used for comparison of multiple compounds or to yield preliminary data for definitive in vitro studies.

References

  1. Obach, S: Glycerolysis of Acyl Glucuronides as an Artifact of In Vitro Drug Metabolism Incubations. DMD August 2009 vol. 37 no. 8 1581-1586

Scientific Content

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