Chronic Continuous Cocaine Infusion in Rats: Effect on Urine Cocaine, Ecgonine Methylester and Benzoylecgonine Concentrations and Bolus-dose Cocaine Pharmacokinetics

Abstract

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 microg mL(-1) to 2.5+/-0.5, 10.5+/-1.8 and 11.8+/-1.5 microg mL(-1) in the high-dose group and from 1.0+/-0-2, 7.8+/-1.5 and 6.3+/-0.1 microg mL(-1) to 0.5+/-0.1, 4.0+/-0.6 and 3.1+/-0.4 microg 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 point) 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.

The effect of chronic cocaine administration on hemodynamic stability and neurohumoral mediators during isoflurane anesthesia and shock in rats

“…Urine produced during this period (3–5 ml) was collected in a glass beaker, which contained 200 μl of saturated NaF and stored at −20°C for subsequent analysis. (Some of these data were also used to investigate the effect of chronic cocaine infusion on cocaine pharmacokinetics and urine metabolite concentrations in the rat (13)). On day 13 after urine sampling, the internal jugular catheter was constricted by the ligature previously placed for this purpose to interrupt further cocaine administration.…”

Revisiting a physiologically based pharmacokinetic model for cocaine with a forensic scope

“…33 The model predicts a total clearance of 334.07 mL min −1 kg −1 which exceeds the value reported in the literature (range 51-204 mL min −1 kg −1 ). 45,[47][48][49] Distribution volume (V d ) is another parameter which might be useful as it's been reported previously; 50 however, attempts at experimental estimation of this parameter have shown differences due to the method of estimation and the use of arterial, or venous samples. 38,44,47,48,51 The values for V d range from 0.9 Regarding benzoylecgonine pharmacokinetics in rats, concentrations time-course predicted for benzoylecgonine in plasma and the brain show a brain/plasma ratio <1 after the first minute post-administration.…”