Chronic continuous cocaine infusion in rats: Effect on urine cocaine, ecgonine methylester and benzoylecgonine concentrations and bolus-dose cocaine pharmacokinetics

The aim of this study was to determine the effect of chronic cocaine infusion on urine cocaine, ecgonine methylester and benzoylecgonine concentrations to establish if they varied with dose and duration of cocaine administration. Male rats were continuously infused with cocaine at either 6 or 18 mg kg^-1 daily for 13 days. Three urine samples taken over the course of the infusion period showed that cocaine, ecgonine methylester and benzoylecgonine concentrations varied with the dose administered and the duration of administration. Cocaine, ecgonine methylester and benzoylecgonine concentrations were 2-3 times greater in the high-dose group than the low-dose group at each sampling time point. These decreased, respectively, from 7.0±1.1, 26.7±4.5 and 29.5±5.4 μg mL^-1 to 2.5±0.5, 10.5±1.8 and 11.8±1.5 μg mL^-1 in the high-dose group and from 1.0±0.2, 7.8±1.5 and 6.3±0.1 μg mL^-1 to 0.5±0.1, 4.0±0.6 and 3.1±0.4 μg mL^-1 in the low-dose group (P < 0.05) over the infusion period. We also studied the pharmacokinetic and metabolic profile of an intravenous bolus dose of 2.5 mg kg^-1 cocaine hydrochloride after a similar cocaine infusion in rats. Cocaine pharmacokinetics and the profile of ecgonine methylester, benzoylecgonine and norcocaine were no different from rats chronically infused with saline for the same period. Altered cocaine metabolism could not explain the effect of the duration of cocaine infusion on altered metabolite concentrations in urine. Ecgonine methylester/benzoylecgonine urine concentration ratios did not alter with duration of infusion (1.2±0.2 and 1.1±0.2 in the high-dose group at the first and last time) and were not affected by the dose of cocaine (1.3±0.6 and 1.2±0.1 at corresponding times in the low-dose group (P > 0.05)). We conclude that chronic cocaine infusion does not alter cocaine metabolism. This was not reflected by absolute cocaine metabolite urine concentrations, which varied with time, but was represented by urine ecgonine methyl ester/benzoylecgonine concentration ratios.