title: Buprenorphine alters desmethylflunitrazepam disposition and flunitrazepam toxicity in rats.
abstract: 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.
authors.affiliation: INSERM U705, CNRS, UMR7157, Université Paris-Descartes, Paris F-75018, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pirnay
authors.forename: Bruno
authors.initials: B
authors.lastname: Megarbane
authors.forename: Xavier
authors.initials: X
authors.lastname: Declèves
authors.forename: Patricia
authors.initials: P
authors.lastname: Risède
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Borron
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bouchonnet
authors.forename: Bérangère
authors.initials: B
authors.lastname: Perrin
authors.forename: Marcel
authors.initials: M
authors.lastname: Debray
authors.forename: Nathalie
authors.initials: N
authors.lastname: Milan
authors.forename: Tania
authors.initials: T
authors.lastname: Duarte
authors.forename: Ivan
authors.initials: I
authors.lastname: Ricordel
authors.forename: Frédéric J
authors.initials: FJ
authors.lastname: Baud
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001711:Biotransformation; D002047:Buprenorphine / Q000008:administration & dosage / Q000633:toxicity*; D002245:Carbon Dioxide / Q000097:blood; D004347:Drug Interactions; D005445:Flunitrazepam / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D018757:GABA Modulators / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D006863:Hydrogen-Ion Concentration; D007262:Infusions, Intravenous; D008297:Male; D010100:Oxygen / Q000097:blood; D012123:Pulmonary Ventilation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012131:Respiratory Insufficiency / Q000097:blood / Q000139:chemically induced* / Q000503:physiopathology
chemical_list: D000701:Analgesics, Opioid; D018757:GABA Modulators; C069164:N-desmethylflunitrazepam; D002245:Carbon Dioxide; D002047:Buprenorphine; D005445:Flunitrazepam; C036343:7-aminoflunitrazepam; D010100:Oxygen