Studies on Metabolic Pathways of Cocaine and Its Metabolites Using Microsome Preparations from Rat Organs

• Published in: Chemical research in toxicology Vol. 16; no. 3; pp. 375 - 381
• Main Authors: Toennes, Stefan W, Thiel, Markus, Walther, Michael, Kauert, Gerold F
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.03.2003
• Subjects: 3-Hydroxy-benzoylecgonine; Animals; benzoylecgonine; benzoylnorecgonine; Brain - metabolism; cocaethylene; Cocaine - analogs & derivatives; Cocaine - blood; Cocaine - metabolism; Cocaine - urine; ecgonine ethyl ester; ecgonine methyl ester; Gas Chromatography-Mass Spectrometry; Hydrolysis; Kidney - metabolism; Lung - metabolism; Male; Microsomes - drug effects; Microsomes - metabolism; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; N-Hydroxy-norcocaine; norcocaethylene; norcocaine; Oxidation-Reduction; Rats; Rats, Sprague-Dawley; Tissue Distribution
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx025580n

Cocaine metabolism has been studied previously with respect to the formation of predominant hydrolytic or hepatotoxic metabolites via oxidative pathways. In the present study, cocaine and eight of its metabolites (norcocaine, ecgonine methyl ester, benzoylecgonine, benzoylnorecgonine, 3-hydroxy-benzoylecgonine, cocaethylene, norcocaethylene, and ecgonine ethyl ester) were incubated with microsomes from rat liver, kidney, lung, and brain. Qualitative analysis of the metabolites produced was performed using solid phase extraction (SPE), trimethylsilylation, and GC/MS. It was found that the metabolites with a free carboxylic group (e.g., benzoylecgonine) were not further oxidized by microsomal enzymes and their presence in urine or blood may therefore be due to hydrolysis of the respective alkylated entities. Although microsomes from all organs exhibited oxidative metabolism, significant differences were noted. Kidney microsomes produced essentially the same results as liver, but aryl hydroxylated metabolites were not found in incubations with lung and brain microsomes. N-Hydroxy-norcocaine was found only in traces with brain microsomes. It appears that cocaine is converted to N-hydroxy-norcocaine (which is the precursor of toxic metabolites) not only in the liver but also in other organs of rat. This might be relevant in the development of lung toxicity observed in smokers of cocaine (“crack”).