Rate of onset of inhibition of gut-wall and hepatic CYP3A by clarithromycin

Sara K. Quinney, Srikar R. Malireddy, Raj Vuppalanchi, Mitchell A. Hamman, Naga Chalasani, J. Christopher Gorski, Stephen D. Hall

Research output: Contribution to journalArticle

16 Scopus citations


Aims: To determine the extent and time-course of hepatic and intestinal cytochrome P450 3A (CYP3A) inactivation due to the mechanism-based inhibitor clarithromycin. Methods: Intestinal and hepatic CYP3A inhibition was examined in 12 healthy volunteers following the administration of single and multiple doses of oral clarithromycin (500 mg). Intestinal biopsies were obtained under intravenous midazolam sedation at baseline and after the first dose, on days 2-4, and on days 6-8 of the clarithromycin treatment. The formation of 1′-hydroxymidazolam in biopsy tissue and the serum 1′- hydroxymidazolam:midazolam ratio were indicators of intestinal and hepatic CYP3A activity, respectively. Results: Intestinal CYP3A activity decreased by 64 % (p = 0.0029) following the first dose of clarithromycin, but hepatic CYP3A activity did not significantly decrease. Repeated dosing of clarithromycin caused a significant decrease in hepatic CYP3A activity (p = 0.005), while intestinal activity showed little further decline. The CYP3A5 or CYP3A4*1B genotype were unable to account for inter-individual variability in CYP3A activity. Conclusions: Following the administration of clarithromycin, the onset of hepatic CYP3A inactivation is delayed compared to that of intestinal CYP3A. The time-course of drug-drug interactions due to clarithromycin will vary with the relative contribution of intestinal and hepatic CYP3A to the clearance and bioavailability of a victim substrate.

Original languageEnglish (US)
Pages (from-to)439-448
Number of pages10
JournalEuropean Journal of Clinical Pharmacology
Issue number3
StatePublished - Mar 1 2013


  • Clarithromycin
  • CYP3A
  • Intestine
  • Mechanism-based inactivation
  • Midazolam

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

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