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

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, no...

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Published in:Toxicology and applied pharmacology 2006-12, Vol.217 (3), p.352-362
Main Authors: Hreiche, Raymond, Mégarbane, Bruno, Pirnay, Stéphane, Borron, Stephen W., Monier, Claire, Risède, Patricia, Milan, Nathalie, Descatoire, Véronique, Pessayre, Dominique, Baud, Frédéric J.
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Addictive behaviors
Adult and adolescent clinical studies
Animals
Biological and medical sciences
BLOOD
Buprenorphine
Buprenorphine - analogs & derivatives
Buprenorphine - blood
Buprenorphine - pharmacokinetics
Buprenorphine - toxicity
CARBON DIOXIDE
Cardiology and cardiovascular system
Cytochrome P-450 CYP3A - biosynthesis
Cytochrome P450
DEATH
DEXAMETHASONE
Dexamethasone - pharmacology
Drug addiction
Drug addictions
Emerging diseases
Enzyme Induction
Glucocorticoids - pharmacology
HEROIN
Human health and pathology
Infectious diseases
Injections, Intraperitoneal
Life Sciences
LIQUID COLUMN CHROMATOGRAPHY
LIVER
Liver - drug effects
Liver - enzymology
Liver metabolism
MAGNESIUM 30
Male
MASS SPECTROSCOPY
Medical sciences
METABOLISM
Narcotics - pharmacokinetics
Narcotics - toxicity
Norbuprenorphine
PARTIAL PRESSURE
Plethysmography
POISONING
Psychology. Psychoanalysis. Psychiatry
Psychopathology. Psychiatry
Pulmonary Ventilation - drug effects
Pulmonary Ventilation - physiology
Pulmonology and respiratory tract
RATS
Rats, Sprague-Dawley
Respiratory depression
Respiratory Function Tests
Respiratory Insufficiency - chemically induced
Respiratory Insufficiency - physiopathology
Respiratory Insufficiency - prevention & control
SOLVENTS
THERAPY
Toxicology
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Summary: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.
ISSN:0041-008X
1096-0333
DOI:10.1016/j.taap.2006.09.011