The role of ketamine on plasma cocaine pharmacokinetics in rat

Ketamine has gained attention recently because of re-emergence of its abuse especially in combination with cocaine. When more than one drug is present simultaneously, the potential for drug--drug interaction exists, which can be pharmacokinetic, pharmacodynamic or both in nature. The objective of this study was to investigate the effect of ketamine on plasma cocaine pharmacokinetics to assess the role that the kinetic component may play in the interaction of these agents. Moreover, the effect of repetitive administration of ketamine pretreatment on the pharmacokinetics of cocaine was addressed. Male Sprague-Dawley rats were treated with cocaine alone (5 mg/kg i.v.), ketamine alone (100 mg/kg by gavage), or ketamine followed by cocaine (the same routes and doses). Blood samples were withdrawn at different time points post-injection and analyzed for determination of cocaine, its metabolites (benzoylecgonine and norcocaine) and ketamine. The results demonstrated that ketamine caused a significant decrease in cocaine's area under the curve (AUC) and elimination half-life while its total clearance was increased. The AUC of benzoylecgonine was increased by 1.5-fold after the combination compared with cocaine alone. However, cocaine did not affect ketamine's pharmacokinetic parameters. In the pretreatment study, ketamine was given orally for 3 days, followed 18 h later by a single i.v. of cocaine. Further enhancement of cocaine metabolism occurred with the appearance of norcocaine. This investigation revealed that ketamine enhances cocaine metabolism and may affect its toxicological profile.