Dose-response cocaine pharmacokinetics and metabolite profile following intravenous administration and arterial sampling in unanesthetized, freely moving male rats

Abstract

Despite the wealth of experimental data on cocaine abuse, there are no published dose-response pharmacokinetic studies with bolus i.v. cocaine injection in the male rat. The present study examined the pharmacokinetics of arterial plasma concentrations of cocaine and metabolite profile [benzoylecgonine (BE), ecgonine methyl ester (EME), norcocaine (NC)] following a single i.v. injection of 0.5, 1.0, or 3.0 mg/kg cocaine. Male Sprague-Dawley rats (N = 25) were anesthetized and surgically instrumented with both jugular vein (drug administration) and carotid artery (blood withdrawal) catheters and allowed to recover for at least 24 h. Arterial plasma samples (200 microliters) were obtained at eight time points (0.5, 1.5, 2.5, 10, 20, 30 min) following i.v. bolus injection (15-s injection, 15-s flush) and analyzed by single ion monitoring using GC/MS. Nonlinear regression and noncompartmental pharmacokinetic analysis were employed. Mean +/- SEM peak plasma concentrations of cocaine occurred at 30 s in a dose-response manner (370 +/- 14,755 +/- 119,2553 +/- 898 ng/ml for 0.5, 1.0, and 3.0 mg/kg groups, respectively). T1/2 alpha was < 1 min for all groups, but inversely related to dose. T1/2 beta was independent of dose 13.3 +/- 1.6, 13.0 +/- 1.5, and 12.0 +/- 2.0 min for 0.5, 1.0, and 3.0 mg/kg groups, respectively). MRT (16.0, 15.9, 14.5 min), VdSS (3.3, 3.2, and 2.8 l/kg), and ClTOT (204, 201, and 195 ml/min/kg) also provided little evidence of dose-dependent effects. Although the metabolic profile of i.v. cocaine was similarly ordered for all dose groups (BE > EME > NC), a quantitative shift in metabolite profile was evident as a function of increasing dose. This metabolic shift, perhaps attributable to saturation of plasma and liver esterases, suggests that the recently reported pharmacodynamic effects positively correlated with i.v. cocaine dose are unlikely attributable to NC, a minor but pharmacologically active metabolite. In sum, the i.v. pharmacokinetic profile in rats is distinct from that observed via the SC, IP, and PO routes of administration and offers the potential to provide a reasonable clinically relevant rodent model.

FIG. 1

The concentration (mean ± SEM) vs. time curves were proportional to dose for IV cocaine administered as a bolus injection to unanesthetized, freely moving adult male rats. Arterial samples were drawn, beginning immediately after the 30-sec IV cocaine bolus (including catheter flush) and periodically throughout 30 min.

FIG. 2

Concentration (mean ± SEM) vs. time curves for cocaine and major (BE) as well as minor metabolites (EME and NC) are shown for the animals that received an IV bolus injection of 3 mg/kg cocaine. The relative ordering of the metabolites indicated that BE was the primary metabolite, with average EME values approximately 1/10 that of BE and average NC values approximately 1/40 that of BE.

FIG. 3

A dose-dependent shift in metabolite profile is illustrated as indexed by the area under the concentration (mean ± SEM) vs. time curve from T₀ to T₃₀. Although the AUC for the concentration vs. time function from T₀ to T₃₀ for each of the metabolites was similarly ordered for all dose groups (BE > EME > NC), a significant shift in metabolite concentrations was evident as a function of increasing cocaine dose. Whereas BE was increased, both EME and NC were depressed at the 3.0 mg/kg dose.