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

Journal Article · Fri Dec 15 04:00:00 EST 2006 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2006.09.011· OSTI ID:20850509

Hreiche, Raymond ^[1]; Megarbane, Bruno ^[2]; Pirnay, Stephane ^[1]; Borron, Stephen W ^[1]; Monier, Claire ^[1]; Risede, Patricia ^[1]; Milan, Nathalie ^[3]; Descatoire, Veronique ^[4]; Pessayre, Dominique ^[4]; Baud, Frederic J ^[1]

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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)
3. Laboratoire de Toxicologie, Prefecture de Police de Paris, 75012 Paris (France)
4. INSERM U481, Faculte de Medecine Xavier Bichat, 75018 Paris (France)

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.

• OSTI ID: 20850509
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 217; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

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