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Methods for Intravenous Self Administration in a Mouse Model
Published on: December 8, 2012
Gender differences in cocaine pharmacokinetics in CF-1 mice
Thomas Visalli1, Rita Turkall, Mohamed S Abdel-Rahman
1Department of Pharmacology and Physiology, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Room I-681, Newark, NJ 07103-2714, USA.
Toxicology Letters
|December 9, 2004
Summary
Cocaine causes liver damage in male mice but not females. Differences in how male and female mice process cocaine and its metabolites explain this gender-specific hepatotoxicity.
Area of Science:
- Pharmacology
- Toxicology
- Metabolism
Background:
- Hepatocellular damage from cocaine is linked to its metabolism via cytochrome P450 to norcocaine.
- This toxicity is observed primarily in male mice, with females showing minimal damage.
Purpose of the Study:
- To investigate the pharmacokinetic and tissue disposition differences of cocaine and its metabolites between male and female mice.
- To elucidate the metabolic role in the observed gender disparity in cocaine-induced hepatotoxicity.
Main Methods:
- Male and female CF-1 mice received oral cocaine hydrochloride (20mg/kg) daily for 7 days.
- Plasma and tissue (liver, heart, brain, kidney) concentrations of cocaine and metabolites (norcocaine, benzoylecgonine, ecgonine methyl ester, ecgonine) were analyzed over time.
Main Results:
- Cocaine's plasma elimination half-life was approximately three times longer in males than females.
- Hydrolysis metabolites (benzoylecgonine, ecgonine methyl ester, ecgonine) were higher in female tissues.
- Norcocaine, a key metabolite in hepatotoxicity, was detected only in male tissues.
Conclusions:
- Gender-specific differences in cocaine pharmacokinetics and metabolite biodisposition contribute to the observed sex difference in cocaine hepatotoxicity.
- Metabolic pathways and resulting tissue distribution of cocaine metabolites are critical factors in its toxicity profile.
