Interaction between midazolam and clarithromycin in the elderly

The cytochrome P450 3A enzymes (CYP3A4 and CYP3A5) participate in the biotransformation of approximately half of the drugs that undergo metabolic clearance in human adults. CYP3A4 is highly expressed in the liver and the epithelium of the small intestine and represents on average 30% of total hepatic CYP protein [1] and 33–87% of intestinal CYP [2]. CYP3A5 exhibits a polymorphic expression pattern with high expression in 10–30% of Whites [3, 4] and is clinically important in the disposition of some CYP3A substrates such as tacrolimus and sirolimus [5, 6]. CYP3A enzymes metabolize a broad array of structurally diverse compounds, including macrolide antibiotics, benzodiazepines, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, calcium channel blockers and human immunodeficiency virus protease inhibitors, and consequently are at the centre of many clinically significant drug interactions. Clarithromycin is a widely used macrolide antibiotic that is a potent inhibitor of CYP3A4 in vitro and in vivo and appears to exert inhibition by an irreversible mechanism. We have previously shown that clarithromycin irreversibly inhibits midazolam hydroxylation in intestinal biopsy tissue obtained from pretreated, young, healthy subjects [7]. An important consequence of this irreversible mechanism is that the inhibition remains for up to 10 days after discontinuation of the inhibitor; this time delay is determined by the elimination half-life of CYP3A4 [8]. We have used the simultaneous intravenous (i.v.)/oral (p.o.) midazolam dosing paradigm to demonstrate that clarithromycin exerts a sex-dependent inhibition of intestinal and hepatic CYP3A in young, healthy subjects [9]. Clinically important consequences of CYP3A inhibition by clarithromycin include excessive sedation following benzodiazepine administration, increased concentrations of ciclosporin A [10–12] and increased risk of nifedipine-induced vasodilatory shock [13]. However the extent of inhibition of CYP3A at hepatic and intestinal sites by potent inhibitors has not previously been examined in the elderly. Elderly patients are more likely to be taking multiple medications and there is a corresponding increase in the likelihood of drug–drug interactions. It has been estimated that >75% of drug–drug interactions occur in persons >50 years old [14]. Although expression of CYP3A proteins does not appear to change with age [15, 16], elderly persons may exhibit altered clearance of CYP3A substrates for a variety of reasons, including disease and altered tissue perfusion and structure. The disposition of CYP3A inhibitors may also be altered in the elderly particularly when renal excretion is an important route of elimination. The renal clearance and total clearance of clarithromycin are significantly decreased in elderly persons with reduced creatinine clearance [17]. However, the drug interaction consequences of the resulting increased exposure to inhibitor have not been previously addressed. Thus, this study was designed to examine the contribution of intestinal and hepatic CYP3A inhibition to the interaction between midazolam and clarithromycin in the elderly, and the effect of sex on the pharmacokinetics of midazolam and extent of interaction were evaluated.