Abstract
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 β-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.
Footnotes
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Send reprint requests to: David J. Greenblatt, M.D., Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Ave., Boston, MA 02111. E-mail: dj.greenblatt{at}tufts.edu
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↵1 This work was supported in part by Grants MH-34223, DA-05258, and RR-00054 from the Department of Health and Human Services and by a grant-in-aid from Pharmacia and Upjohn, Kalamazoo, Michigan. L.L.v.M. is the recipient of a Scientist Development Award (K21-MH-01237) from the Department of Health and Human Services.
- Abbreviations:
- EEG
- electroencephalogram
- DSST
- digit symbol substitution test
- AUC
- area under the plasma concentration-versus-time curve
- RAUC
- area under pharmacodynamic effect curve divided by area under plasma concentration curve
- KEO
- first-order rate constant representing exit of drug from hypothetical effect compartment
- t1/2KEO
- apparent half-life of equilibration corresponding toKEO
- Received September 21, 1999.
- Accepted January 24, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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