Quantitative evaluation of hepatic and intestinal induction of CYP3A in clinical practice

Abstract

1. This is the first report quantitatively evaluating the clinical induction of CYP3A in the liver and the intestine.

2. To evaluate hepatic induction, we collected literature data on endogenous biomarkers of hepatic CYP3A induction which we then used to calculate the fold-induction (inducer-mediated change in biomarker level). Literature data on decreases in the area under the curve (AUC) of alfentanil, a CYP3A substrate, caused by CYP3A inducers were also collected. We used the hepatic intrinsic clearance of alfentanil to calculate the hepatic induction ratio (inducer-mediated change in intrinsic clearance). For intestinal induction, the intestinal bioavailability (F_g) of alfentanil was used to calculate the intestinal induction ratio. We determined in vivo maximum induction (E_max) and the average unbound plasma concentration (C_av,u) required for half the maximum induction (EC₅₀) for inducers using an E_max model analysis.

3. In our results, fold-induction was comparable to the induction ratio at several inducer concentrations, and almost the maximum induction was achieved by a therapeutic dose. Induction ratios in the intestine were similar to the liver.

4. Our findings suggest that, by knowing only hepatic induction ratios for common inducers, we can quantitatively predict the decreases in the AUC of substrates by CYP3A induction.

Keywords:

• Induction
• CYP3A4
• clinical
• drug–drug interaction
• quantitative evaluation
• induction in human liver and small intestine

Acknowledgments

The authors thank Mr. Jacob Davis for his useful advice in the preparation and language editing of this paper.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.