Cocaine, norcocaine, ecgonine methylester and benzoylecgonine pharmacokinetics in the rat

We have compared the pharmacokinetics of bolus dose cocaine administration with that of its three most important metabolites; norcocaine, ecgonine met hylester, and benzoylecgonine and assessed whether kinetics are dose depend ent at two equimolar doses equivalent to cocaine hydrochloride 2.5 and 5mg/ kg respectively. Forty-nine male Sprague-Dawley rats were randomly divided into 8 groups to receive iv either high (14.7 umol/kg) (HI) or low (7.3 umo l/kg) (LO) bolus doses of cocaine or one of its metabolites. Arterial blood samples for cocaine and metabolite analysis were taken repetitively over t he next 3 h. Equimolar bolus doses of these congeners showed biexponential plasma concentration decay curves which were fitted to a two compartment mo del and subjected to noncompartmental analysis. The plasma concentration ti me profiles were significantly different for the HI and LO doses administer ed for each congener. The elimination half-lives of cocaine and norcocaine were similar (28-33 min), that for ecgonine methylester (60-71 min) was app roximately twice this and for benzoylecgonine was 40-44 min. Cocaine cleara nce (155-158 ml/kg/min) was found to be in the range found in other rat stu dies. Ecgonine methylester clearance and benzoylecgonine clearance were fou nd to be one quarter and one eighth of this value respectively. The pharmac okinetic profile of these congeners was not dose dependent when the two dos es administered were compared.