Investigators: JO Miners, RA McKinnon
The use of in vitro drug metabolism kinetic data to predict human drug disposition parameters in vivo for those compounds eliminated by cytochrome P450 has become widespread in recent years. However, the validity of the extrapolation of in vitro data for drugs metabolised by UDP-glucuronosyltransferases (UGT) remains unknown. Similarly, human liver microsomal 'phenotyping' studies to identify those UGT isoforms responsible for the glucuronidation of any given drug in humans has not proved possible due to the unavailability of isoform specific 'probes'.
In vitro models, based on human liver microsomal kinetic data, are being developed for drugs eliminated by UGT which allow the prediction of key pharmacokinetic parameters (eg hepatic clearance) in vivo, and the extent of altered drug clearance due to inhibitory drug-drug interactions.
In silico, or computer-aided molecular modelling, is being used to develop three dimensional quantitative structure activity relationships (3D-QSARS) to identify the active site binding requirements of substrates for individual UGT isoforms. In turn, this will allow the UGT isoform responsible for the metabolism of any newly discovered drug to be predicted without recourse to laboratory-based procedures.