Quantitative evaluation of hepatic and intestinal induction of CYP3A in clinical practice
Creators: name: Tsutsui, Haruka
name: Kato, Motohiro
name: Kuramoto, Shino
name: Sekiguchi, Nobuo
name: Shindoh, Hidetoshi
name: Ozeki, Kazuhisa
Publisher: name: Taylor & Francis
Year: 2020
Subjects: subject: Biophysics
subject: Biochemistry
subject: Space Science
subject: 29999 Physical Sciences not elsewhere classified
subject: FOS: Physical sciences
subject: FOS: Physical sciences
subject: Microbiology
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Cell Biology
subject: Molecular Biology
subject: Physiology
subject: Pharmacology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: FOS: Chemical sciences
subject: Science Policy
subject: Cancer
subject: Inorganic Chemistry
subject: 60506 Virology

description: This is the first report quantitatively evaluating the clinical induction of CYP3A in the liver and the intestine.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<sub>g</sub>) of alfentanil was used to calculate the intestinal induction ratio. We determined in vivo maximum induction (E<sub>max</sub>) and the average unbound plasma concentration (C<sub>av,u</sub>) required for half the maximum induction (EC<sub>50</sub>) for inducers using an E<sub>max</sub> model analysis.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.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. This is the first report quantitatively evaluating the clinical induction of CYP3A in the liver and the intestine. 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<sub>g</sub>) of alfentanil was used to calculate the intestinal induction ratio. We determined in vivo maximum induction (E<sub>max</sub>) and the average unbound plasma concentration (C<sub>av,u</sub>) required for half the maximum induction (EC<sub>50</sub>) for inducers using an E<sub>max</sub> model analysis. 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. 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.