Azithromycin appears to have effect on triazolam pharmacokinetics.
Inhibition of Triazolam Clearance by Macrolide Antimicrobial Agents: In Vitro Correlates and Dynamic Consequences
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Study Design
In an in vitro model using human liver microsomes, 250 mumol/L triazolam was incubated with ascending concentrations (0 to 250 mumol/L of troleandomycin, azithromycin, erythromycin, and clarithromycin. In a randomized, double-blind, 5-trial clinical pharmacokinetic-pharmacodynamic study, 12 volunteers received 0.125 mg triazolam orally, together with placebo, azithromycin, erythromycin, or clarithromycin. In a fifth trial they received placebo plus placebo.
Study Results
ean 50 inhibitory concentrations versus 4-hydroxytriazolam formation in vitro were as follows: 3.3 mumol/L troleandomycin, 27.3 mumol/L erythromycin, 25.2 mumol/L clarithromycin, and greater than 250 mumol/L azithromycin. Apparent oral clearance of triazolam when given with placebo or azithromycin was nearly identical (413 and 416 mL/min), as were peak plasma concentrations (1.25 and 1.32 ng/mL) and elimination half-life (2.7 and 2.6 hours). Apparent oral clearance was significantly reduced (P .05) during erythromycin and clarithromycin trials (146 and 95 mL/min). Peak plasma concentration was correspondingly increased, and elimination half-life was prolonged. The effects of triazolam on dynamic measures were nearly identical when triazolam was given with placebo or azithromycin, but benzodiazepine agonist effects were enhanced during erythromycin and clarithromycin trials.
Study Conclusions
The in vitro model identifies macrolides that may impair triazolam clearance. Anticipated interactions, and their pharmacodynamic consequences in volunteer subjects, were verified in vivo.
References
Greenblatt DJ. Inhibition of triazolam clearance by macrolide antimicrobial agents: in vitro correlates and dynamic consequences. Clin Pharmacol Ther. 1998; 3: 278-85.
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