Impact of Intracellular Concentrations on Metabolic Drug-Drug Interaction Studies.

ABSTRACT: Accurate prediction of drug-drug interactions (DDI) is a challenging task in drug discovery and development. It requires determination of enzyme inhibition in vitro which is highly system-dependent for many compounds. The aim of this study was to investigate whether the determination of intracellular unbound concentrations in primary human hepatocytes can be used to bridge discrepancies between results obtained using human liver microsomes and hepatocytes. Specifically, we investigated if Kp_uu could reconcile differences in CYP enzyme inhibition values (K_i or IC₅₀). Firstly, our methodology for determination of Kp_uu was optimized for human hepatocytes, using four well-studied reference compounds. Secondly, the methodology was applied to a series

SUBMITTER: Treyer A 

PROVIDER: S-EPMC6581936 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature