UGT Inhibition Studies in the Presence or Absence of Alamethicin Evaluation of UGT1A1 and UGT2B7

UGT Inhibition Studies in the Presence or Absence of Alamethicin Evaluation of UGT1A1 and UGT2B7

Published:  10/21/2015 12:45:00 PM

UGT Inhibition Studies in the Presence or Absence of Alamethicin: Evaluation of UGT1A1 and UGT2B7 Inhibition in Human Liver Microsomes and Recombinant Enzymes

The importance of evaluating new drug candidates for the potential to inhibit
UDP-glucuronosyltransferase (UGT) enzymes
has recently garnered scientific and regulatory interest. To date, several published studies have demonstrated the importance of various membrane disruptors (e.g., alamethicin or CHAPS) and other exogenous protein sources (e.g., BSA or FABP) for improvement of the in vitro to in vivo prediction of metabolic clearance due to glucuronidation (Fisher et al., 2000, Rowland et al., 2007, Walsky et al., 2012). The active site of UGTs faces the lumen of the endoplasmic reticulum, and typically a detergent is used to disrupt the membrane allowing for maximal enzyme activity. However, there is little data available to evaluate the impact of these exogenous factors on evaluating inhibition of UGT enzymes in vitro

In the present study, we examined the effect of alamethicin, a pore forming agent, on UGT1A1 and UGT2B7 inhibition (IC50) in Human Liver Microsomes (HLM) and recombinant UGTs by a variety of commonly used UGT inhibitors with the goal of optimizing assays conditions.

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