DOI: 10.1097/00000539-199902001-00360
,
Issn Print: 0003-2999
Publication Date: 1999/02/01
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INTRODUCTION: The major metabolites of cocaine may contribute to its toxicity as norcocaine (nor) is a hepatotoxin while benzoylecgonine (be) has been implicated in delayed onset coronary vasospasm. In the dog, bolus dose cocaine kinetics have been demonstrated to be dose dependent in the range, 2-4mg/kg while in the rat 3mg/kg was not different from 1mg/kg. To date there is no comprehensive comparison of the kinetics of cocaine and its metabolites nor an evaluation of dose dependency for these congeners in the range established for dogs.
METHODS: Forty-eight (48) male Sprague-Dawley rats ([similar]400g) fitted with femoral artery and venous catheters, 24 hours prior to study, were randomly divided into 8 groups to receive iv either high (14.7 umol/kg) (HI) or low (7.3 umole/kg) (LO) equimolar bolus doses of cocaine or one of its metabolites, nor, ecgonine methylester (eme) or be on the study day. After this, arterial blood samples for cocaine and metabolite analysis were taken repetitively over the next 3 hours for analysis using a validated HPLC method. Plasma sample concentrations for each individual animal were fitted to a two compartment open model using WinNonlin (SCI Software, NC) and the derived kinetic data grouped and compared using the two tailed t-test. Grouped plasma decay curves were compared using repeated measures ANOVA. P < 0.05 was held to be significant.
RESULTS: Equimolar bolus doses of cocaine or its metabolites (equivalent to 2.5 and 5mg/kg of cocaine hydrochloride) showed biexponential decay curves which were significantly different for the HI and LO doses administered for each congener, Figure 1.
In addition Cmax and AUC were significantly and proportionately (not shown,[ns]) increased for HI vs LO doses for all congeners. Despite this, there were no differences in clearance or volumes of distribution [ns] or half-lives (except t1/2 alpha for cocaine) (Table 1) between HI and LO groups indicating dose independent kinetics over this range in the rat. Cocaine and nor kinetics were similar while t1/2 beta was prolonged for eme and be.
DISCUSSION: The data indicate that cocaine and cocaine metabolite kinetics are dose independent in the rat over the range studied.
