Pharmacokinetic analysis of the metabolism of cocaine to norcocaine and N-hydroxynorcocaine in mice

Abstract

Cocaine is hepatotoxic in humans and is a very effective hepatotoxin in the mouse. Previous in vitro studies have shown that the mixed function oxidase system is very important in the metabolism of cocaine to the hepatotoxic species. Activation of cocaine to the cytotoxic species is thought to proceed through the N-demethylation and subsequent N-hydroxylation of the bridgehead amine. The in vivo metabolism of cocaine involves not only oxidative but also hydrolytic mechanisms. Therefore the principle aim of this study was to establish a system in which the in vivo metabolism of cocaine to norcocaine and N-hydroxynorcocaine could be determined. The in vivo metabolism of acutely administered cocaine to norcocaine and N-hydroxynorcocaine was assessed in two inbred mouse strains; one that is relatively sensitive to cocaine hepatotoxicity but shows little enhancement in toxicity when pretreated with phenobarbital (DBA/2lbg), and one that shows little hepatotoxicity unless pretreated with phenobarbital (C57BL/6lbg). Although no significant differences between the strains were seen in the pharmacokinetics of cocaine, the half-life of both norcocaine and N-hydroxynorcocaine was significantly longer in DBA mice. Accordingly, the area under the curve values for hepatic norcocaine and N-hydroxynorcocaine were approximately 5- and 3-fold greater, respectively, in DBA as compared with C57BL mice. The higher levels of both norcocaine and N-hydroxynorcocaine in the DBA mouse are consistent with previously established differences in cocaine hepatotoxicity in these strains of mice. Pretreatment of C57BL mice with phenobarbital prolonged the half-life of norcocaine and N-hydroxynorcocaine 5- to 8-fold over C57BL control values.(ABSTRACT TRUNCATED AT 250 WORDS)