Metabolism of norcocaine,N-hydroxy norcocaine and cocaine-N-oxide in the rat

Abstract

1. The metabolism of [³H]norcocaine, N-hydroxy[³H]norcocaine and cocaine-N-oxide has been investigated in rats after i.v. injection. 2. The biological t_1/2 of norcocaine (dose 2mg/kg i.v.) in plasma, liver and brain were 0·4, 1·6, 0·5 h, respectively and the compound was not detectable in the central nervous system 6 h after injection. The % dose of norcocaine excreted unchanged in urine and faeces in 96 h were 0·7 and 1·0, respectively. Benzoylnorecgonine, norecgonine, norecgonine methyl ester and an unidentified compound were excreted in urine. 3. The biological t_1/2 of N-hydroxynorcocaine (5 mg/kg i.v.) in brain and plasma were 0·3, 1·6 h respectively and only 1·3 and 1·6% of dose were excreted unchanged in urine and faeces in 96 h. N-Hydroxybenzoylnorecgonine and N-hydroxynorecgonine methyl ester were the major urinary metabolites. N-hydroxynorcocaine was not metabolized to norcocaine in vitro by liver microsomes. Doses of > 7·5 mg/kg i.v. resulted in death of rats by cardiorespiratory arrest. 4. Cocaine-N-oxide (50mg/kg i.v.) yielded ecgonine-N-oxide methyl ester as its major metabolite; other minor metabolites were cocaine (0·5%), norcocaine (1%), benzoylecgonine, ecgonine, ecgonine-N-oxide, along with minor amounts of unmetabolized compound. Lethality of cocaine-N-oxide (100mg/kg i.v.) was possibly due to metabolism to norcocaine and cocaine.