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(-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(-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(-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.
authors.affiliation: INSERM U705, CNRS UMR 7157, Université Paris 7, Université Paris 5, Hôpital Fernand Widal, 75010 Paris, France.
authors.forename: Raymond
authors.initials: R
authors.lastname: Hreiche
authors.forename: Bruno
authors.initials: B
authors.lastname: Mégarbane
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pirnay
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Borron
authors.forename: Claire
authors.initials: C
authors.lastname: Monier
authors.forename: Patricia
authors.initials: P
authors.lastname: Risède
authors.forename: Nathalie
authors.initials: N
authors.lastname: Milan
authors.forename: Véronique
authors.initials: V
authors.lastname: Descatoire
authors.forename: Dominique
authors.initials: D
authors.lastname: Pessayre
authors.forename: Frédéric J
authors.initials: FJ
authors.lastname: Baud
mesh_terms: D000818:Animals; D002047:Buprenorphine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology*; D004790:Enzyme Induction; D005938:Glucocorticoids / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D009294:Narcotics / Q000493:pharmacokinetics / Q000633:toxicity*; D012123:Pulmonary Ventilation / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012129:Respiratory Function Tests; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D005938:Glucocorticoids; D009294:Narcotics; D002047:Buprenorphine; C043585:norbuprenorphine; D003907:Dexamethasone; D051544:Cytochrome P-450 CYP3A