Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats

Objectives: The recommended zolpidem starting dose was lowered in females (5mg vs 10mg) 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 CMAX (112.4 vs 68.1 ug/L) and AUC (537.8 vs 231.8 hr*ug/L) than uncastrated males. Castration induced an earlier TMAX (0.25 vs 1 hr), greater CMAX (109.1 vs 68.1 ug/L), and a corresponding AUC increase (339.7 vs 231.8 hr*ug/L). Administration of disulfiram caused more drastic CMAX and TMAX 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.