Urinary 6 beta-Hydroxycortisol/Cortisol Ratio Most Highly Correlates With Midazolam Clearance Under Hepatic CYP3A Inhibition and Induction in Females: A Pharmacometabolomics Approach

Abstract

Endogenous metabolites of cytochrome P450 (CYP3A) are useful in predicting drug-drug interactions between in vivo CYP3A inhibitors and inducers for clinical applications of CYP3A substrate drugs. This study aimed to develop predictable markers of the magnitude of hepatic CYP3A induction and inhibition in healthy female subjects using pharmacometabolomics. Twelve female subjects received midazolam during three study phases: 1 mg midazolam (control phase), 1 mg midazolam after pretreatment with 400 mg ketoconazole once daily for 4 days (CYP3A inhibition phase), and 2.5 mg midazolam after pretreatment with 600 mg rifampicin once daily for 10 days (CYP3A induction phase). Throughout the study, blood samples were collected 24 h after midazolam administration and urine samples at 12-h intervals during the 24 h before and after midazolam administration for the analysis of endogenous steroid metabolites. A statistical model was generated to predict midazolam clearance using measurements of endogenous metabolites associated with the inhibition and induction of CYP3A. Mean midazolam clearance decreased to similar to 20% of control levels during the inhibition phase and increased more than 2-fold during the induction phase. Of the urine and plasma metabolites measured, the 6 beta-hydroxycortisol/cortisol ratio was most significantly correlated with midazolam clearance during hepatic CYP3A inhibition and induction. Our results suggest that the urinary 6 beta-hydroxycortisol/cortisol ratio is the best predictor of hepatic CYP3A activity under both maximal inhibition and maximal induction. Furthermore, the predictive model including 6 beta-hydroxycortisol/cortisol as a covariate could be applied to predict the magnitude of CYP3A-mediated drug interactions.