Centre for Drug Candidate Optimisation - Disciplines

Drug Metabolism

Rapid metabolism is a major limiting feature of many new drug candidates and can lead to low oral bioavailability, a short in vivo half-life, production of potentially active or toxic metabolites and the potential for drug-drug interactions through enzyme inhibition/induction.

The Centre assesses drug metabolism in a number of different ways:

• assessment of the in vitro biotransformation of parent compound using either microsomes or hepatocytes to assess both Phase I and II reactions
• comparison of metabolite profiles using microsomes from multiple species with identification of metabolites by LC-MS/MS
• examination of the kinetics of metabolite formation and the potential saturation and/or inhibition of these processes
• screening for potential drug interactions by use of a high throughput assay for inhibition of common cytochrome P450 (CYP) isoforms and by the use of isoform-specific substrates to calculate in vitro inhibition constants
• identification of metabolising enzymes using cDNA-expressed human cytochrome P450 or UGT isoforms and screening for Pgp affinity using an ATPase-assay
• detection of time dependent or mechanism-based enzyme inhibition
• detection of metabolites in plasma, urine, and bile following in vivo administration to laboratory animals, or in situ using an isolated perfused liver model

The data and information generated from these studies can be used to identify major metabolites and metabolising enzymes, identify metabolically labile functional moieties within a structural series, and provide a basis for structural modifications to reduce metabolic lability. With some necessary assumptions, in vitro studies can also be used to predict in vivo clearance and provide inter-species metabolic profiling to guide species selection for initial toxicity testing.

The Centre has a number of drug metabolism assays that are currently under development including an enzyme induction assay, and assays that assess the formation of reactive and/or toxic CYP450-mediated metabolites.