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Urinary 6β-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 ∼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 6β-hydroxycortisol/cortisol ratio was most significantly correlated with midazolam clearance during hepatic CYP3A inhibition and induction. Our results suggest that the urinary 6β-hydroxycortisol/cortisol ratio is the best predictor of hepatic CYP3A activity under both maximal inhibition and maximal induction. Furthermore, the predictive model including 6β-hydroxycortisol/cortisol as a covariate could be applied to predict the magnitude of CYP3A-mediated drug interactions.

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ACKNOWLEDGMENTS

This work was supported by a National Research Foundation of Korea grant funded by the Korean government (MEST) (NRF-2014R1A2A2A01005541) and by grant no. 04-2012-0620 from the Seoul National University Hospital Research Fund. We thank Ms. Hwa-Suk Kim and Ms. Geum-Jwa Ryu for performing the genotyping analysis and for quantifying midazolam and its metabolites. We also acknowledge Ms. Sang-Sook Yoon and Ms. Sinae Kim for assisting with the clinical trials and performing the statistical analyses.

Author contributions

Ms. L. Y. Ahn, Ms. J. Lee, and Drs. K-H. Shin, K-S. Yu, I-J. Jang, and J-Y. Cho participated in study design and data analysis. Dr. M. H. Choi and Dr. J-Y. Moon contributed to steroid profiling and data analysis. All authors participated in the drafting and review of this manuscript.

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Correspondence to Joo-Youn Cho.

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Kwang-Hee Shin and Li Young Ahn contributed equally to this work.

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Shin, KH., Ahn, L.Y., Choi, M.H. et al. Urinary 6β-Hydroxycortisol/Cortisol Ratio Most Highly Correlates With Midazolam Clearance Under Hepatic CYP3A Inhibition and Induction in Females: A Pharmacometabolomics Approach. AAPS J 18, 1254–1261 (2016). https://doi.org/10.1208/s12248-016-9941-y

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KEYWORDS

  • CYP3A
  • drug interaction
  • female
  • metabolite
  • metabolic phenotyping