Enzyme kinetics of uridine diphosphate glucuronosyltransferases (UGTs)

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 bi-substrate reaction that requires the aglycone and a cofactor, UDPGA. Accumulating evidence suggests that the bi-substrate reaction follows a compulsory-order ternary mechanism. To simplify the kinetic modelling of glucuronidation reactions in vitro, UDPGA 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 in experimental design and data interpretation. Assessing drug-drug interactions (DDIs) involving UGT inhibition remains challenging. However, the increasing availability of UGT enzyme-specific substrate and inhibitor "probes" provides the prospect for more reliable reaction phenotyping and assessment of DDI potential. Although extrapolation of the in vitro intrinsic clearance of a glucuronidated drug often under-predicts 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 (IVIVE).