In vitro studies and in silico predictions of fluconazole and CYP2C9 genetic polymorphism impact on siponimod metabolism and pharmacokinetics.

ABSTRACT: PURPOSE:The purpose of the study is to investigate the enzyme(s) responsible for siponimod metabolism and to predict the inhibitory effects of fluconazole as well as the impact of cytochrome P450 (CYP) 2C9 genetic polymorphism on siponimod pharmacokinetics (PK) and metabolism. METHODS:In vitro metabolism studies were conducted using human liver microsomes (HLM), and enzyme phenotyping was assessed using a correlation analysis method. SimCYP, a physiologically based PK model, was developed and used to predict the effects of fluconazole and CYP2C9 genetic polymorphism on siponimod metabolism. Primary PK parameters were generated using the SimCYP and WinNonlin software. RESULTS:Correlation analysis suggested that CYP2C9 is the main enzyme responsible for siponimod metabolism in humans. Compar

SUBMITTER: Jin Y 

PROVIDER: S-EPMC5849655 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature