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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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

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
Journal of Pharmacology and Experimental Therapeutics May 2000, 293 (2) 435-443;
David J. Greenblatt
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Jerold S. Harmatz
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Lisa L. von Moltke
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C. Eugene Wright
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Anna Liza B. Durol
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Lisa M. Harrel-Joseph
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Richard I. Shader
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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

  • 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

  • ↵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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Journal of Pharmacology and Experimental Therapeutics: 293 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 2
1 May 2000
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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

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
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 435-443;

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

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

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
Journal of Pharmacology and Experimental Therapeutics May 1, 2000, 293 (2) 435-443;
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