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

Cody J Peer,Karim Calis,Emmanuel O Fadiran,Angela Men,Pamela Scott,Tristan M Sissung,Alesia Holly,Ronald Farkas,Jonathan D Strope,Marjorie Jenkins,Jagan Parepally,William H Theodore,Ariel M Ley,Shaunna Beedie

doi:10.3389/fphar.2016.00260

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 CMAX (112.4 vs. 68.1 ug/L) and AUC (537.8 vs. 231.8 h∗ug/L) than uncastrated males. Castration induced an earlier TMAX (0.25 vs. 1 h), greater CMAX (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 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.Conclusion: These findings indicate that sex differences in zolpidem PK are influenced by variation in the expression of ADH/ALDH due to gonadal androgens.

Highlights

Zolpidem is a gamma-aminobutyric acid (GABA) agonist that is indicated for the treatment of insomnia characterized by difficulties with sleep initiation
The major circulating metabolite is zolpidem phenyl 4-carboxylic acid (ZPCA; 72–86%), with zolpidem 6-carboxylic acid (ZCA) making up roughly ∼10% of the administered dose (Gillet, 1991; Pichard et al, 1995). It is currently unknown which alcohol dehydrogenases (ADHs)/aldehyde dehydrogenases (ALDHs) enzyme classes are responsible for the metabolism of zolpidem, and whether gastric ADH/ALDH pathways contribute to zolpidem disposition
The PK of zolpidem in males and females treated with vehicle (1% carboxy methylcellulose (CMC)) were compared to demonstrate the existence of sexual dimorphism in zolpidem clearance our animal model

Summary

Introduction

Zolpidem is a gamma-aminobutyric acid (GABA) agonist that is indicated for the treatment of insomnia characterized by difficulties with sleep initiation. To address sex-related adverse events, the FDA reduced the recommended initial dose by half in females (Food and Drug Administration [FDA], 2008). The major circulating metabolite is zolpidem phenyl 4-carboxylic acid (ZPCA; 72–86%), with zolpidem 6-carboxylic acid (ZCA) making up roughly ∼10% of the administered dose (Gillet, 1991; Pichard et al, 1995). It is currently unknown which ADH/ALDH enzyme classes are responsible for the metabolism of zolpidem, and whether gastric ADH/ALDH pathways contribute to zolpidem disposition. Along with certain cytochromes P450, such as CYP3A that acts synergistically with other enzymes in the gastric mucosa of humans and animals (Yoon et al, 2011), the ADH/ALDH enzyme pathway is likely the major contributor to the bioavailability and elimination of zolpidem

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