Interaction between midazolam and clarithromycin in the elderly

• Published in: British journal of clinical pharmacology 2008-01, Vol.65 (1), p.98-109
• Main Authors: Quinney, Sara K., Haehner, Barbara D., Rhoades, Melissa B., Lin, Zhen, Gorski, J. Christopher, Hall, Stephen D.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Anti-Anxiety Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacokinetics; Biological and medical sciences; clarithromycin; Clarithromycin - pharmacokinetics; CYP3A; Cytochrome P-450 Enzyme System - metabolism; cytochrome P450; Drug Interactions; elderly; Female; Humans; Injections, Intravenous; Intestines - enzymology; Liver - enzymology; Male; Medical sciences; midazolam; Midazolam - pharmacokinetics; Pharmacology. Drug treatments; Regression Analysis
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2007.02970.x

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Clarithromycin is a mechanism‐based inhibitor of CYP3A that has been shown to inhibit midazolam hydroxylation in young, healthy subjects. • Elderly persons exhibit altered metabolism of a variety of drugs, including clarithromycin. • However, the consequences of increased exposure to an inhibitor drug on CYP3A activity have not been addressed. WHAT THIS STUDY ADDS • This study utilized intravenous and oral midazolam as in vivo probes to examine the effect of clarithromycin on intestinal and hepatic CYP3A activity. • Although clarithromycin concentrations are greater in elderly individuals than in young, healthy volunteers, intestinal and hepatic CYP3A enzymes are inhibited to a similar extent as in the young. 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, 15N3‐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, 15N3‐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