Related Experiment Video
Updated: Mar 15, 2026

Modeling Alcohol Consumption in Rodents Using Two-Bottle Choice Home Cage Drinking and Microstructural Analysis
Published on: November 8, 2024
Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats
Cody J Peer1, Jonathan D Strope2, Shaunna Beedie2
1Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda MD, USA.
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.
Related Concept Videos
CNS Depressants: Alcohol and Nicotine
Sedatives and Hypnotics: Overview
Sedative-hypnotics are categorized into barbiturates, benzodiazepines (BZDs), and non-benzodiazepines or Z-drugs. These drugs work by suppressing central nervous system activity, and this suppression is dose-dependent. Older sedative medications, like barbiturates, follow a linear curve in...
Depressants
Alcohol is a common depressant that can induce a sense of relaxation and reduced inhibition at low doses. Contrary to its occasional...
Sedatives and Hypnotics Drugs: Benzodiazepines
Benzodiazepines work by enhancing the effects of the inhibitory neurotransmitter GABA. They bind to the GABAA receptor, increasing its affinity for GABA, which opens chloride...
Alcohols from Carbonyl Compounds: Reduction
Catalytic hydrogenation is similar to the reduction of an alkene or alkyne by adding H2 across the pi bond in the presence of transition metal catalysts like Raney Ni, Pd–C, Pt, or Ru. Aldehydes and ketones can be reduced by this method, often under mild to moderate heat (25–100°C) and...

