Journal
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
Volume 65, Issue 1, Pages 98-109Publisher
WILEY
DOI: 10.1111/j.1365-2125.2007.02970.x
Keywords
clarithromycin; CYP3A; cytochrome P450; elderly; midazolam
Categories
Funding
- NCRR NIH HHS [M01 RR00750, M01 RR000750] Funding Source: Medline
- NIGMS NIH HHS [R56 GM067308, T32GM08425, T32 GM008425, GM067308, R01 GM067308] Funding Source: Medline
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR000750] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R56GM067308, T32GM008425, R01GM067308] Funding Source: NIH RePORTER
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AIM To assess the relative contribution of intestinal and hepatic CYP3A inhibition to the interaction between the prototypic CYP3A substrate midazolam and clarithromycin in the elderly. METHODS On day 1, 16 volunteers (eight male, eight female) aged 65 - 75 years weighing 59 - 112 kg received simultaneous doses of midazolam intravenously (i.v.) (0.05 mg kg(-1) over 30 min) and orally (p.o.) (3.5 mg of a stable isotope, N-15(3)-midazolam). Starting on day 2, clarithromycin 500 mg was administered orally twice daily for 7 days. On day eight, i.v. and p.o. doses of midazolam were administered 2 h after the final clarithromycin dose. Serum and urine samples were assayed for midazolam, N-15(3)-midazolam and metabolites by gas chromatography/mass spectometry. RESULTS Men and women exhibited similar i.v. (30.4 vs. 36.0 l h(-1)) and p.o. (119 vs. 124 l h(-1)) clearances of midazolam. Midazolam hepatic availability was significantly (P=0.006) greater in men [0.79, 95% confidence interval (CI) 0.75, 0.84] than in women (0.66, 95% CI 0.59, 0.73), but midazolam intestinal availability (0.39 vs. 0.55) was not different. Following clarithromycin dosing, a significant decrease in systemic (33.2 l h(-1) to 11.5 l h(-1)) and oral (121 l h(-1) to 17.4 l h(-1)) midazolam clearance occurred. Oral, hepatic and intestinal availability was significantly increased after clarithromycin dosing from 0.34 to 0.72, 0.73 to 0.91 and 0.47 to 0.79, respectively. Clarithromycin administration led to an increase in the AUC of midazolam by 3.2-fold following i.v. dosing and 8.0-fold following p.o. dosing. Similar effects were observed for males and females. CONCLUSIONS Intestinal and hepatic CYP3A inhibition by clarithromycin significantly reduces the clearance of midazolam in the elderly.
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