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Title: Dexamethasone hepatic induction in rats subsequently treated with high dose buprenorphine does not lead to respiratory depression

Abstract

In humans, asphyxic deaths and severe poisonings have been attributed to high-dosage buprenorphine, a maintenance therapy for heroin addiction. However, in rats, intravenous buprenorphine at doses up to 90 mg kg{sup -1} was not associated with significant effects on arterial blood gases. In contrast, norbuprenorphine, the buprenorphine major cytochrome P450 (CYP) 3A-derived metabolite, is a potent respiratory depressant. Thus, our aim was to study the consequences of CYP3A induction on buprenorphine-associated effects on resting ventilation in rats. We investigated the effects on ventilation of 30 mg kg{sup -1} buprenorphine alone or following cytochrome P450 (CYP) 3A induction with dexamethasone, using whole body plethysmography (N = 24) and arterial blood gases (N = 12). Randomized animals in 4 groups received sequential intraperitoneal dosing with: (dexamethasone [days 1-3] + buprenorphine [day 4]), (dexamethasone solvent [days 1-3] + buprenorphine [day 4]), (dexamethasone [days 1-3] + buprenorphine solvent [day 4]), or (dexamethasone solvent [days 1-3] + buprenorphine solvent [day 4]). Buprenorphine alone caused a significant rapid and sustained increase in the inspiratory time (P < 0.001), without significant effects on the respiratory frequency, the tidal volume, the minute volume, or arterial blood gases. In dexamethasone-pretreated rats, there was no significant alteration in the respiratorymore » parameters, despite CYP3A induction and significant increase of the ratio of plasma norbuprenorphine-to-buprenorphine concentrations. In conclusion, dexamethasone did not modify the effects of 30 mg kg{sup -1} buprenorphine on rat ventilation. Our results suggest a limited role of drug-mediated CYP3A induction in the occurrence of buprenorphine-attributed respiratory depression in addicts.« less

Authors:
 [1];  [2];  [1];  [3];  [1];  [4];  [1];  [1];  [5];  [6];  [6];  [1];  [3]
  1. INSERM U705, CNRS UMR 7157, Universite Paris 7, Universite Paris 5, Hopital Fernand Widal, 75010 Paris (France)
  2. INSERM U705, CNRS UMR 7157, Universite Paris 7, Universite Paris 5, Hopital Fernand Widal, 75010 Paris (France) and Assistance Publique-Hopitaux de Paris, Hopital Lariboisiere, Reanimation Medicale et Toxicologique, Universite Paris 7, 75010 Paris (France). E-mail: bruno-megarbane@wanadoo.fr
  3. (France)
  4. (United States)
  5. Laboratoire de Toxicologie, Prefecture de Police de Paris, 75012 Paris (France)
  6. INSERM U481, Faculte de Medecine Xavier Bichat, 75018 Paris (France)
Publication Date:
OSTI Identifier:
20850509
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 217; Journal Issue: 3; Other Information: DOI: 10.1016/j.taap.2006.09.011; PII: S0041-008X(06)00341-3; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BLOOD; CARBON DIOXIDE; DEATH; DEXAMETHASONE; HEROIN; LIQUID COLUMN CHROMATOGRAPHY; LIVER; MAGNESIUM 30; MASS SPECTROSCOPY; METABOLISM; PARTIAL PRESSURE; POISONING; RATS; SOLVENTS; THERAPY

Citation Formats

Hreiche, Raymond, Megarbane, Bruno, Pirnay, Stephane, Laboratoire de Toxicologie, Prefecture de Police de Paris, 75012 Paris, Borron, Stephen W., Department of Surgery, University of Texas Health Science Center, San Antonio, TX 78229, Monier, Claire, Risede, Patricia, Milan, Nathalie, Descatoire, Veronique, Pessayre, Dominique, Baud, Frederic J., and Assistance Publique-Hopitaux de Paris, Hopital Lariboisiere, Reanimation Medicale et Toxicologique, Universite Paris 7, 75010 Paris. Dexamethasone hepatic induction in rats subsequently treated with high dose buprenorphine does not lead to respiratory depression. United States: N. p., 2006. Web. doi:10.1016/j.taap.2006.09.011.
Hreiche, Raymond, Megarbane, Bruno, Pirnay, Stephane, Laboratoire de Toxicologie, Prefecture de Police de Paris, 75012 Paris, Borron, Stephen W., Department of Surgery, University of Texas Health Science Center, San Antonio, TX 78229, Monier, Claire, Risede, Patricia, Milan, Nathalie, Descatoire, Veronique, Pessayre, Dominique, Baud, Frederic J., & Assistance Publique-Hopitaux de Paris, Hopital Lariboisiere, Reanimation Medicale et Toxicologique, Universite Paris 7, 75010 Paris. Dexamethasone hepatic induction in rats subsequently treated with high dose buprenorphine does not lead to respiratory depression. United States. doi:10.1016/j.taap.2006.09.011.
Hreiche, Raymond, Megarbane, Bruno, Pirnay, Stephane, Laboratoire de Toxicologie, Prefecture de Police de Paris, 75012 Paris, Borron, Stephen W., Department of Surgery, University of Texas Health Science Center, San Antonio, TX 78229, Monier, Claire, Risede, Patricia, Milan, Nathalie, Descatoire, Veronique, Pessayre, Dominique, Baud, Frederic J., and Assistance Publique-Hopitaux de Paris, Hopital Lariboisiere, Reanimation Medicale et Toxicologique, Universite Paris 7, 75010 Paris. Fri . "Dexamethasone hepatic induction in rats subsequently treated with high dose buprenorphine does not lead to respiratory depression". United States. doi:10.1016/j.taap.2006.09.011.
@article{osti_20850509,
title = {Dexamethasone hepatic induction in rats subsequently treated with high dose buprenorphine does not lead to respiratory depression},
author = {Hreiche, Raymond and Megarbane, Bruno and Pirnay, Stephane and Laboratoire de Toxicologie, Prefecture de Police de Paris, 75012 Paris and Borron, Stephen W. and Department of Surgery, University of Texas Health Science Center, San Antonio, TX 78229 and Monier, Claire and Risede, Patricia and Milan, Nathalie and Descatoire, Veronique and Pessayre, Dominique and Baud, Frederic J. and Assistance Publique-Hopitaux de Paris, Hopital Lariboisiere, Reanimation Medicale et Toxicologique, Universite Paris 7, 75010 Paris},
abstractNote = {In humans, asphyxic deaths and severe poisonings have been attributed to high-dosage buprenorphine, a maintenance therapy for heroin addiction. However, in rats, intravenous buprenorphine at doses up to 90 mg kg{sup -1} was not associated with significant effects on arterial blood gases. In contrast, norbuprenorphine, the buprenorphine major cytochrome P450 (CYP) 3A-derived metabolite, is a potent respiratory depressant. Thus, our aim was to study the consequences of CYP3A induction on buprenorphine-associated effects on resting ventilation in rats. We investigated the effects on ventilation of 30 mg kg{sup -1} buprenorphine alone or following cytochrome P450 (CYP) 3A induction with dexamethasone, using whole body plethysmography (N = 24) and arterial blood gases (N = 12). Randomized animals in 4 groups received sequential intraperitoneal dosing with: (dexamethasone [days 1-3] + buprenorphine [day 4]), (dexamethasone solvent [days 1-3] + buprenorphine [day 4]), (dexamethasone [days 1-3] + buprenorphine solvent [day 4]), or (dexamethasone solvent [days 1-3] + buprenorphine solvent [day 4]). Buprenorphine alone caused a significant rapid and sustained increase in the inspiratory time (P < 0.001), without significant effects on the respiratory frequency, the tidal volume, the minute volume, or arterial blood gases. In dexamethasone-pretreated rats, there was no significant alteration in the respiratory parameters, despite CYP3A induction and significant increase of the ratio of plasma norbuprenorphine-to-buprenorphine concentrations. In conclusion, dexamethasone did not modify the effects of 30 mg kg{sup -1} buprenorphine on rat ventilation. Our results suggest a limited role of drug-mediated CYP3A induction in the occurrence of buprenorphine-attributed respiratory depression in addicts.},
doi = {10.1016/j.taap.2006.09.011},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 217,
place = {United States},
year = {Fri Dec 15 00:00:00 EST 2006},
month = {Fri Dec 15 00:00:00 EST 2006}
}