The contribution of intestinal and hepatic CYP3A to the interaction between midazolam and clarithromycin

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Updated: Oct 28, 2026

An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
08:59

An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment

Published on: December 3, 2020

J C Gorski1, D R Jones, B D Haehner-Daniels

  • 1Division of Clinical Pharmacology, Indiana University School of Medicine, Wishard Memorial Hospital, Indianapolis 46202-2879, USA.

Clinical Pharmacology and Therapeutics
|September 5, 1998
PubMed
Abstract

Insights

Clarithromycin significantly increases oral midazolam availability by inhibiting both intestinal and hepatic CYP3A enzymes. The intestine plays a major role in this drug interaction, influencing variability in midazolam metabolism.

Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Drug Interactions

Background:

  • Cytochrome P450 3A (CYP3A) enzymes are crucial for metabolizing numerous drugs.
  • Understanding the sites of drug metabolism (liver vs. intestine) is key to predicting drug-drug interactions.
  • Midazolam and clarithromycin are prototypic substrates and inhibitors of CYP3A, respectively.

Purpose of the Study:

  • To determine the relative contribution of intestinal and hepatic CYP3A inhibition to the interaction between midazolam and clarithromycin.
  • To investigate the impact of clarithromycin on midazolam pharmacokinetics.

Main Methods:

  • A pharmacokinetic study involving 16 healthy volunteers (8 male, 8 female).
  • Administration of intravenous and oral midazolam before and after a 7-day course of clarithromycin.
  • Analysis of midazolam and its metabolites in blood and urine using gas chromatography-mass spectrometry.

Main Results:

  • Clarithromycin significantly reduced midazolam's systemic clearance and increased its oral bioavailability.
  • Both intestinal and oral midazolam availability were significantly enhanced by clarithromycin.
  • Female subjects exhibited a greater extent of drug interaction compared to male subjects.

Conclusions:

  • The intestine is a significant site for the interaction between oral midazolam and clarithromycin, alongside the liver.
  • Interindividual variability in the first-pass metabolism of CYP3A substrates like midazolam is largely influenced by intestinal enzyme activity.

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