Buprenorphine alters desmethylflunitrazepam disposition and flunitrazepam toxicity in rats. - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Toxicological Sciences Année : 2008

Buprenorphine alters desmethylflunitrazepam disposition and flunitrazepam toxicity in rats.

Résumé

High-dosage buprenorphine (BUP) consumed concomitantly with benzodiazepines (BZDs) including flunitrazepam (FZ) may cause life-threatening respiratory depression despite a BUP ceiling effect and BZDs' 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 pretreatment did not alter plasma FZ and 7-AFZ kinetics in Sprague-Dawley rats infused with 40 mg/kg FZ over 30 min, whereas resulting in a three-fold increase in the area under the curve (AUC) of DMFZ concentrations compared with control (p < 0.01). In contrast, BUP did not significantly modify plasma DMFZ concentrations after intravenous infusion of 7 mg/kg DMFZ, whereas resulting in a similar peak concentration to that generated from 40 mg/kg FZ administration. Regarding the effects on ventilation, BUP (30 mg/kg) as well as its combination with FZ (0.3 mg/kg) significantly increased PaCO(2), whereas only BUP/FZ combination decreased PaO(2) (p < 0.001). Interestingly, FZ (40 mg/kg) but not DMFZ (40 mg/kg) significantly increased PaCO(2) (p < 0.05), whereas DMFZ but not FZ decreased PaO(2) (p < 0.05). Thus, decrease in PaO(2) appears related to BUP-mediated effects on DMFZ disposition, although increases in PaCO(2) 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.

Dates et versions

hal-00525494 , version 1 (12-10-2010)

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Stéphane Pirnay, Bruno Mégarbane, Xavier Declèves, Patricia Risède, Stephen W Borron, et al.. Buprenorphine alters desmethylflunitrazepam disposition and flunitrazepam toxicity in rats.. Toxicological Sciences, 2008, 106 (1), pp.64-73. ⟨10.1093/toxsci/kfn163⟩. ⟨hal-00525494⟩
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