INHIBITION OF TRIAZOLAM CLEARANCE BY MACROLIDE ANTIMICROBIAL AGENTS -IN-VITRO CORRELATES AND DYNAMIC CONSEQUENCES

Background: Macrolide antimicrobial agents may impair hepatic clearanc e of drugs metabolized by cytochrome P4503A isoforms. Potential intera ctions of triazolam, a substrate metabolized almost entirely by cytoch rome P4503A in humans, with 3 commonly prescribed macrolides were iden tified using an in vitro metabolic model. The actual interactions, and their pharmacodynamic consequences, were verified in a controlled cli nical study. Methods: In an in vitro model using human liver microsome s, 250 mu mol/L triazolam was incubated with ascending concentrations (0 to 250 mu mol/L) of troleandomycin, azithromycin, erythromycin, and clarithromycin. In a randomized, double-blind, 5-trial clinical pharm acokinetic-pharmacodynamic study, 12 volunteers received 0.125 mg tria zolam orally, together with placebo, azithromycin, erythromycin, or cl arithromycin. In a fifth trial they received placebo plus placebo. Res ults: Mean 50% inhibitory concentrations versus 4-hydroxytriazolam for mation in vitro were as follows: 3.3 mu mol/L troleandomycin, 27.3 mu mol/L erythromycin, 25.2 mu mol/L clarithromycin, and greater than 250 mu mol/L azithromycin, Apparent oral clearance of triazolam when give n with placebo or azithromycin was nearly identical (413 and 416 mL/mi n), as were peak plasma concentrations (1.25 and 1.32 ng/mL) and elimi nation half-life (2.7 and 2.6 hours). Apparent oral clearance was sign ificantly reduced (P < .05) during erythromycin and clarithromycin tri als (146 and 95 mL/min). Peak plasma concentration was correspondingly increased, and elimination half-life was prolonged. The effects of tr iazolam on dynamic measures were nearly identical when triazolam was g iven with placebo or azithromycin, but benzodiazepine agonist effects were enhanced during erythromycin and clarithromycin trials. Conclusio n: The in vitro model identifies macrolides that may impair triazolam clearance. Anticipated interactions, and their pharmacodynamic consequ ences in volunteer subjects, were verified in vivo.