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

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

Research output: Contribution to journalArticle

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Abstract

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
Pages (from-to)439-448
Number of pages10
JournalEuropean Journal of Clinical Pharmacology
Volume69
Issue number3
DOIs
StatePublished - Mar 2013

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Cytochrome P-450 CYP3A
Clarithromycin
Liver
Midazolam
Biopsy
Drug Interactions
Biological Availability
Healthy Volunteers

Keywords

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

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Rate of onset of inhibition of gut-wall and hepatic CYP3A by clarithromycin. / Quinney, Sara; Malireddy, Srikar R.; Vuppalanchi, Raj; Hamman, Mitchell A.; Chalasani, Naga; Gorski, J. Christopher; Hall, Stephen D.

In: European Journal of Clinical Pharmacology, Vol. 69, No. 3, 03.2013, p. 439-448.

Research output: Contribution to journalArticle

Quinney, Sara ; Malireddy, Srikar R. ; Vuppalanchi, Raj ; Hamman, Mitchell A. ; Chalasani, Naga ; Gorski, J. Christopher ; Hall, Stephen D. / Rate of onset of inhibition of gut-wall and hepatic CYP3A by clarithromycin. In: European Journal of Clinical Pharmacology. 2013 ; Vol. 69, No. 3. pp. 439-448.
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abstract = "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.",
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AU - Vuppalanchi, Raj

AU - Hamman, Mitchell A.

AU - Chalasani, Naga

AU - Gorski, J. Christopher

AU - Hall, Stephen D.

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N2 - 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.

AB - 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.

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