Toxicological Sciences 62, 148-154 (2001)
Copyright © 2001 by the Society of Toxicology
SAFETY EVALUATION |
Lack of Effect of Single High Doses of Buprenorphine on Arterial Blood Gases in the Rat
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* INSERM U26, Université Paris VII, Hôpital Fernand Widal, 75475 Paris, France;
Department of Emergency Medicine, George Washington University Hospital, Washington, DC 20037;
Laboratoire de Biochimie-Toxicologie, Hôpital Fernand Widal, 75475 Paris, France;
Laboratoire de Biomathématiques, Université Paris V, UFR Pharmacie, 75006 Paris, France; and
¶ International Toxicology Consultants, LLC, 2000 L Street NW, Suite 200, Washington, DC 20036–4997
High dose buprenorphine, a potent semisynthetic agonist-antagonist for opiate receptors, is now used in substitution treatment of human heroin addiction. Deaths have been reported in addicts misusing buprenorphine. We determined the median lethal dose (LD50) and studied the effects of high doses of intravenous buprenorphine on arterial blood gases in rats. Male Sprague-Dawley rats were administered buprenorphine intravenously to determine the LD50 using the up-and-down method. Subsequently, catheterized groups of 10 restrained rats received no drug, saline, acid-alcohol aqueous solvent (required to dissolve buprenorphine at a high concentration), or 3, 30, or 90 mg/kg of buprenorphine intravenously. Serial arterial blood gases were obtained over 3 h. The LD50 determined in triplicate was 146.5 mg/kg (median of 3 series, range: 142.6–176.5). The mean dose received by surviving animals was 96.9 ± 46.7 mg/kg. There was a significant effect of the acid-alcohol aqueous solvent on arterial blood gases. Excluding the solvent effect, 3, 30, and 90-mg/kg buprenorphine doses had no significant effects on arterial blood gases. The toxicity of intravenous buprenorphine in adult rats, assessed by the LD50, is low. These data are consistent with a wide margin of safety of buprenorphine. The mechanism of death after the intravenous administration of a lethal dose of buprenorphine remains to be determined.
Key Words: buprenorphine; acute toxicity; safety; rats; LD50; arterial blood gas; opioids; heroin substitution; drug abuse.
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