UGT Inhibition

Overview

Glucuronidation is a major pathway of xenobiotic biotransformation in mammalian species, and the reaction is catalyzed by UDP-glucuronosyltransferases (UGTs), which are located predominantly in the endoplasmic reticulum of liver. Since drug-drug interactions 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.

Sekisui XenoTech’s study design evaluates drug candidates as direct-acting inhibitors of UGT enzymes in human liver microsomes. Our study design 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.

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

Sekisui XenoTech's inhibition assays are typically performed with pooled human liver microsomes (pool of 200). This allows the same sample of pooled human liver microsomes (and often the same experimental conditions, for example, protein concentration and incubation time) 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.


Followup Service Offerings

Ki determinations: Determine Ki value for direct inhibition with multiple concentrations of the drug candidate and marker substrate.
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