DOSE-RESPONSE COCAINE PHARMACOKINETICS AND METABOLITE PROFILE FOLLOWING INTRAVENOUS ADMINISTRATION AND ARTERIAL SAMPLING IN UNANESTHETIZED,FREELY MOVING MALE-RATS

Despite the wealth of experimental data on cocaine abuse, there are no published dose-response pharmacokinetic studies with bolus IV cocaine injection in the male rat. The present study examined the pharmacokin etics of arterial plasma concentrations of cocaine and metabolite prof ile [benzoylecgonine (BE), ecgonine methyl ester (EME), norcocaine (NC )] following a single IV injection of 0.5, 1.0, or 3.0 mg/kg cocaine. Male Sprague-Dawley rats (N = 25) were anesthetized and surgically ins trumented with both jugular vein (drug administration) and carotid art ery (blood withdrawal) catheters and allowed to recover for at least 2 4 h. Arterial plasma samples (200 mu l) were obtained at eight time po ints (0.5, 1, 1.5, 2, 5, 10, 20, 30 min) following TV bolus injection (15-s injection, 15-s flush) and analyzed by single ion monitoring usi ng GC/MS. Nonlinear regression and noncompartmental pharmacokinetic an alysis were employed. Mean +/- SEM peak plasma concentrations of cocai ne 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) . T-1/2 proportional to, was < 1 min for all groups, but inversely rel ated to dose. T-1/2 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, respe ctively). MRT (16.0, 15.9, 14.5 min), Vd(ss) (3.3, 3.2, and 2.8 l/kg), and Cl-TOT (204, 201, and 195 ml/min/kg) also provided little evidenc e of dose-dependent effects. Although the metabolic profile of IV coca ine was similarly ordered for all dose groups (BE > EME > NC), a quant itative shift in metabolite profile was evident as a function of incre asing dose. This metabolic shift, perhaps attributable to saturation o f plasma and liver esterases, suggests that the recently reported phar macodynamic effects positively correlated with IV cocaine dose are unl ikely attributable to NC, a minor but pharmacologically active metabol ite. In sum, the IV pharmacokinetic profile in rats is distinct from t hat observed via the SC, IF, and PO routes of administration and offer s the potential to provide a reasonable clinically relevant rodent mod el. (C) 1997 Elsevier Science Inc.