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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 (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 se...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983555/
https://www.ncbi.nlm.nih.gov/pubmed/27574509
http://dx.doi.org/10.3389/fphar.2016.00260
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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.
author_facet 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.
author_sort Peer, Cody J.
collection PubMed
description 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.
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spelling pubmed-49835552016-08-29 Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats 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. Front Pharmacol Pharmacology 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. Frontiers Media S.A. 2016-08-15 /pmc/articles/PMC4983555/ /pubmed/27574509 http://dx.doi.org/10.3389/fphar.2016.00260 Text en Copyright © 2016 Peer, Strope, Beedie, Ley, Holly, Calis, Farkas, Parepally, Men, Fadiran, Scott, Jenkins, Theodore and Sissung. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
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.
Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats
title Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats
title_full Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats
title_fullStr Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats
title_full_unstemmed Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats
title_short Alcohol and Aldehyde Dehydrogenases Contribute to Sex-Related Differences in Clearance of Zolpidem in Rats
title_sort alcohol and aldehyde dehydrogenases contribute to sex-related differences in clearance of zolpidem in rats
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983555/
https://www.ncbi.nlm.nih.gov/pubmed/27574509
http://dx.doi.org/10.3389/fphar.2016.00260
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