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ToxSci Advance Access first published online on August 14, 2008
This version published online on August 21, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn163
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© The Author 2008. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Buprenorphine alters desmethylflunitrazepam disposition and flunitrazepam toxicity in rats

Stéphane Pirnay*,{dagger}, Bruno Megarbane*,{ddagger},1, Xavier Declèves*, Patricia Risède*, Stephen W. Borron§, Stéphane Bouchonnet, Bérangère Perrin{dagger}, Marcel Debray*,||, Nathalie Milan{dagger}, Tania Duarte*, Ivan Ricordel{dagger} and Frédéric J. Baud*,{ddagger}

* INSERM U705, CNRS, UMR7157, Université Paris-Descartes, and Université Paris-Diderot, Paris F-75018, France {dagger} Laboratoire de Toxicologie de l'Institut National de Police Scientifique, Paris F-75012, France {ddagger} Réanimation Médicale et Toxicologique, Hôpital Lariboisière, Paris F-75010, France § Department of Surgery, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, MC 7736, San Antonio, TX 78229, USA DCMR, Ecole Polytechnique, Route de Saclay, 91128 Palaiseau, France || Laboratoire de Biomathématiques, Université Paris-Descartes, 75006 Paris, France

1 To whom correspondence should be addressed at Réanimation Médicale et Toxicologique, Hôpital Lariboisière, 2 Rue Ambroise Paré, 75010 Paris, France. Telephone number: (+33)-1-49-95-89-61, Fax number: (+33)-1-49-95-65-78. E-mail: bruno-megarbane{at}wanadoo.fr

Received June 5, 2008; revision received August 3, 2008; accepted August 4, 2008


  Abstract

High-dosage buprenorphine (BUP) consumed concomitantly with benzodiazepines including flunitrazepam (FZ) may cause life-threatening respiratory depression despite a BUP ceiling effect and benzodiazepines' limited effects on ventilation. However, the mechanism of BUP/FZ interaction remains unknown. We hypothesized that BUP may alter the disposition of FZ active metabolites in vivo, contributing to respiratory toxicity. Plasma FZ, desmethylflunitrazepam (DMFZ), and 7-aminoflunitrazepam (7-AFZ) concentrations were measured using gas chromatography-mass spectrometry. Intravenous BUP 30 mg.kg-1 pretreatment did not alter plasma FZ and 7-AFZ kinetics in Sprague-Dawley rats infused with 40 mg.kg-1 FZ over 30 min, while resulting in a three-fold increase in the area-under-the-curve of DMFZ concentrations compared with control (p<0.01). In contrast, BUP did not significantly modify plasma DMFZ concentrations after intravenous infusion of 7mg.kg-1 DMFZ, while resulting in a similar peak concentration to that generated from 40 mg.kg-1 FZ administration. Regarding the effects on ventilation, BUP (30 mg.kg-1) as well as its combination with FZ (0.3 mg.kg-1) significantly increased PaCO2 while only BUP/FZ combination decreased PaO2 (p<0.001). Interestingly, FZ (40 mg.kg-1) but not DMFZ (40 mg.kg-1) significantly increased PaCO2 (p<0.05), whereas DMFZ but not FZ decreased PaO2 (p<0.05). Thus, decrease in PaO2 appears related to BUP-mediated effects on DMFZ disposition while increases in PaCO2 relate to direct BUP/FZ additive or synergistic dynamic interactions. We conclude that combined high-dosage BUP and FZ is responsible for increased respiratory toxicity in which BUP-mediated alteration in DMFZ disposition may play a significant role.

Key Words: Buprenorphine; Desmethylflunitrazepam; Flunitrazepam; Interaction; Metabolism; Pharmacokinetics.

E-mail addresses: pirnaystephane{at}yahoo.com; bruno-megarbane{at}wanadoo.fr; xavier.decleves{at}univ-paris5.fr; patricia.risede{at}inserm.fr; borron{at}uthscsa.edu; stephane.bouchonnet{at}dcmr.polytechnique.fr; b.perrin{at}wanadoo.fr; marcel.debray{at}univ-paris5.fr; n.Milan{at}yahoo.fr; tania.m.duarte{at}gmail.com; prefpol-labotoxico.directeur{at}wanadoo.fr; frederic.baud{at}lrb.aphp.fr


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