The comparative toxicity of cocaine and its metabolites in conscious rats.
BACKGROUND
The metabolites of cocaine, benzoylecgonine and ecgonine methyl ester, have been considered pharmacologically inactive when administered systemically. However, recent in vitro studies suggest that this may not be true. The current study was designed to evaluate the systemic toxicity of cocaine and its metabolites when administered systemically to awake rats fitted with catheters for long-term monitoring.


METHODS
Cocaine, norcocaine, cocaethylene, benzoylecgonine, and ecgonine methyl ester were infused intravenously to produce sequential behavioral alterations and central nervous system and cardiovascular toxic effects. Arterial blood pressure and heart rate were monitored continuously. Plasma and tissue samples were analyzed for all compounds by capillary gas chromatography-mass spectrometry.


RESULTS
The dose of norcocaine necessary to produce toxic effects was smaller than that of cocaine and cocaethylene. Benzoylecgonine and ecgonine methyl ester did not produce toxic manifestations at infusion rates that produced toxicity in the cocaine, norcocaine, and cocaethylene groups. Furthermore, 30- and 60-fold higher doses of benzoylecgonine and ecgonine methyl ester, respectively, were necessary to produce only mild neurobehavioral changes. Benzoylecgonine was not lethal even at doses 100 times greater than cocaine.


CONCLUSIONS
These results indicate that benzoylecgonine and ecgonine methyl ester are not as toxic as cocaine, norcocaine, or cocaethylene when administered intravenously to pharmacologically naive rats.
Morishima
H O
HO
Department of Anesthesiology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. hom2@columbia.edu
Whittington
R A
RA
Iso
A
A
Cooper
T B
TB
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003042:Cocaine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
C008671:norcocaine; C005618:benzoylecgonine; C066444:cocaethylene; D003042:Cocaine; C034524:ecgonine methyl ester