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UGT Enzyme Inhibition
Glucuronidation is a major pathway of xenobiotic biotransformation in mammalian species. Glucuronidation requires the co-factor UDPGA 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.
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.
UGT1A1 17β-Estradiol 3-glucuronidation
UGT1A4 Trifluoperazine glucuronidation
UGT1A6 1-Naphthol glucuronidation
UGT1A9 Propofol glucuronidation
UGT2B7 Morphine 3-glucuronidation
Dedicated pool of 16 individuals, mixed gender, native human liver microsomes
XenoTech’s inhibition assays are typically performed with a dedicated pool of human liver microsomes characterized to provide Km and Vmax values for each marker substrate reaction. 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.
Typical IC50 incubation conditions
Protein concentration: ≤0.1 mg/mL
Incubation time: 5 minutes
Automation and Analysis
Tecan liquid-handling system or manual incubations available
Validated LC/MS/MS methods
High-throughput Shimadzu autosamplers
Deuterated internal standards for most UGTs
Automated data retrieval and processing
Comprehensive, publication-quality reports
Available as GLP or non-GLP
Direct inhibition IC50 values determined from seven concentrations of the drug candidate.
Ki determinations: determine Ki value for direct inhibition with multiple concentrations of the drug candidate and marker substrate.