Enzyme inhibition for drug-drug interaction (DDI) investigations
Inhibition of cytochrome P450 (CYP) and UGT enzymes is a major cause of clinically relevant drug-drug interactions (see DDI studies).
The inhibitory potential of a test article is assessed by determining its effect on the metabolism of selective probe substrates for human CYP enzymes in pooled human hepatic microsome-based incubations.
Inhibitory enzyme kinetics can be further characterized and the resultant data used to predict whether a clinically significant DDI may occur following administration of the drug.
These studies are recommended by all global regulatory bodies via DDI guidelines to generate data on both reversible (direct) and irreversible (time-dependent) cytochrome P450 inhibition before going to first-in-human (FIH) trials. Inhibition data are used in determining the requirement and scope of clinical DDI studies.