Vol. 293, Issue 2, 435-443, May 2000

Comparative Kinetics and Response to the Benzodiazepine Agonists Triazolam and Zolpidem: Evaluation of Sex-Dependent Differences¹

David J. Greenblatt, Jerold S. Harmatz, Lisa L. von Moltke, C. Eugene Wright, Anna Liza B. Durol, Lisa M. Harrel-Joseph and Richard I. Shader

Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and New England Medical Center, Boston, Massachusetts (D.J.G., J.S.H., L.L.v.M., A.L.B.D., L.M.H.-J., R.I.S.); and Pharmacia and Upjohn Co., Kalamazoo, Michigan (C.E.W.)

Eighteen healthy volunteers (10 men and 8 women) participated in a single-dose, double-blind, three-way crossover pharmacokinetic and pharmacodynamic study. Treatment conditions were 0.25 mg of triazolam, a full-agonist benzodiazepine ligand; 10 mg of zolpidem, an imidazopyridine having relative selectivity for the type 1 benzodiazepine receptor subtype; and placebo. Weight-normalized clearance of triazolam was higher in women than in men (8.7 versus 5.5 ml/min/kg), but the difference was not significant. In contrast, zolpidem clearance was lower in women than in men (3.5 versus 6.7 ml/min/kg, P < .06). Compared to placebo, both active medications produced significant benzodiazepine agonist-like pharmacodynamic effects: sedation, impaired psychomotor performance, impaired information recall, and increased electroencephalographic -amplitude. Effects of triazolam and zolpidem in general were comparable and less than 8 h in duration. There was no evidence of a substantial or consistent sex difference in pharmacodynamic effects or in the kinetic-dynamic relationship, although subtle differences could not be ruled out due to low statistical power. The complete dependence of triazolam clearance on CYP3A activity, as opposed to the mixed CYP participation in zolpidem clearance, may explain the differing sex effects on clearance of the two compounds.