Problems and perspectives of phenotyping for drug-metabolizing enzymes in man.

摘要

Pronounced interindividual differences in drug disposition are mainly caused by differences in the activity of liver drug-metabolizing enzymes. These depend on known and unknown covariates, including genetic as well as environmental factors. Phenotyping, i.e. assessment of enzyme activities in vivo after administration of a test dose, seems to be a promising tool for determining actual metabolic capacities. Although it is a well-established experimental approach, phenotyping has not yet found its way into clinical practice. Main reasons for this are lack of validation for many probes and assays used, complicated procedures, invasiveness, semi-quantitative test results, non-compliance on behalf of the subjects tested, high costs, and lack of prospective clinical studies to assess the benefit of phenotyping for patients. Problems and perspectives of phenotyping are exemplified for the cytochrome P-450 enzymes CYP1A2 and CYP3A4, two major human drug-metabolizing enzymes.