Human hepatocytes and cytochrome P450-selective inhibitors predict variability in human drug exposure more accurately than human recombinant P450s.

ABSTRACT:

Background and purpose

Drugs metabolically eliminated by several enzymes are less vulnerable to variable compound exposure in patients due to drug-drug interactions (DDI) or if a polymorphic enzyme is involved in their elimination. Therefore, it is vital in drug discovery to accurately and efficiently estimate and optimize the metabolic elimination profile.

Experimental approach

CYP3A and/or CYP2D6 substrates with well described variability in vivo in humans due to CYP3A DDI and CYP2D6 polymorphism were selected for assessment of fraction metabolized by each enzyme (fm_CYP ) in two in vitro systems: (i) human recombinant P450s (hrP450s) and (ii) human hepatocytes combined with selective P450 inhibitors. Increases in compound exposure in poor versus extensive CYP2D6

SUBMITTER: Lindmark B 

PROVIDER: S-EPMC5980217 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature