AUTHOR=Peer Cody J. , Strope Jonathan D. , Beedie Shaunna , Ley Ariel M. , Holly Alesia , Calis Karim , Farkas Ronald , Parepally Jagan , Men Angela , Fadiran Emmanuel O. , Scott Pamela , Jenkins Marjorie , Theodore William H. , Sissung Tristan M. TITLE=Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats JOURNAL=Frontiers in Pharmacology VOLUME=7 YEAR=2016 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2016.00260 DOI=10.3389/fphar.2016.00260 ISSN=1663-9812 ABSTRACT=

Objectives: The recommended zolpidem starting dose was lowered in females (5 mg vs. 10 mg) since side effects were more frequent and severe than those of males; the mechanism underlying sex differences in pharmacokinetics (PK) is unknown. We hypothesized that such differences were caused by known sex-related variability in alcohol dehydrogenase (ADH) expression.

Methods: Male, female, and castrated male rats were administered 2.6 mg/kg zolpidem, ± disulfiram (ADH/ALDH pathway inhibitor) to compare PK changes induced by sex and gonadal hormones. PK analyses were conducted in rat plasma and rat brain.

Key findings: Sex differences in PK were evident: females had a higher C_MAX (112.4 vs. 68.1 ug/L) and AUC (537.8 vs. 231.8 h^∗ug/L) than uncastrated males. Castration induced an earlier T_MAX (0.25 vs. 1 h), greater C_MAX (109.1 vs. 68.1 ug/L), and a corresponding AUC increase (339.7 vs. 231.8 h^∗ug/L). Administration of disulfiram caused more drastic C_MAX and T_MAX changes in male vs. female rats that mirrored the effects of castration on first-pass metabolism, suggesting that the observed PK differences may be caused by ADH/ALDH expression. Brain concentrations paralleled plasma concentrations.

Conclusion: These findings indicate that sex differences in zolpidem PK are influenced by variation in the expression of ADH/ALDH due to gonadal androgens.