title: Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  These findings indicate that sex differences in zolpidem PK are influenced by variation in the expression of ADH/ALDH due to gonadal androgens.
authors: Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda MD, USA.
authors: Cody J
authors: CJ
authors: Peer
authors: Molecular Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda MD, USA.
authors: Jonathan D
authors: JD
authors: Strope
authors: Molecular Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda MD, USA.
authors: Shaunna
authors: S
authors: Beedie
authors: Molecular Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda MD, USA.
authors: Ariel M
authors: AM
authors: Ley
authors: Molecular Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda MD, USA.
authors: Alesia
authors: A
authors: Holly
authors: Office of Medical Policy, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring MD, USA.
authors: Karim
authors: K
authors: Calis
authors: Office of New Drugs, Division of Neurology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring MD, USA.
authors: Ronald
authors: R
authors: Farkas
authors: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring MD, USA.
authors: Jagan
authors: J
authors: Parepally
authors: Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring MD, USA.
authors: Angela
authors: A
authors: Men
authors: Office of Women's Health, Office of the Commissioner, Food and Drug Administration, Silver Spring MD, USA.
authors: Emmanuel O
authors: EO
authors: Fadiran
authors: Office of Women's Health, Office of the Commissioner, Food and Drug Administration, Silver Spring MD, USA.
authors: Pamela
authors: P
authors: Scott
authors: Office of Women's Health, Office of the Commissioner, Food and Drug Administration, Silver Spring MD, USA.
authors: Marjorie
authors: M
authors: Jenkins
authors: Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda MD, USA.
authors: William H
authors: WH
authors: Theodore
authors: Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda MD, USA.
authors: Tristan M
authors: TM
authors: Sissung
keywords: drug metabolism; pharmacokinetics; testosterone; zolpidem