To accurately assess the mechanism of involvement of the active metabolite norcocaine in the effects of oral cocaine, it is essential to determine the rate and extent of the formation of norcocaine. Although this study was designed specifically for this aim, it was also of interest to characterize the metabolite kinetics of benzoylecgonine for comparative purpose. We first characterized the pharmacokinetics of cocaine, norcocaine, and benzoylecgonine by the i.v. route of administration; all three drugs decayed biexponentially. These pharmacokinetic estimates were then used for determination of the formation of norcocaine and benzoylecgonine after i.v. and p.o. (20-40 mg/kg) cocaine administration. Although t(1/2alpha), and t(1/2beta) were similar across the three compounds, the values of volume of distribution in the central compartment and clearance for benzoylecgonine were much smaller than those of cocaine and norcocaine. Norcocaine was not detected following i.v. cocaine; however, serum norcocaine concentrations were as high as those of oral cocaine. Both routes of cocaine administration produced benzoylecgonine. A pharmacokinetic model for the metabolite kinetics was proposed by sequentially adding the models that most adequately described the formation of each metabolite to the model of cocaine. For oral cocaine, the absolute bioavailability was 3.48%, whereas 6.04 and 2.26% of cocaine were converted to benzoylecgonine and norcocaine, respectively, during first-pass absorption regardless of dose. Furthermore, the majority of norcocaine and 92% of benzoylecgonine were formed during the first-pass absorption, leaving 8% of benzoylecgonine produced in systemic circulation. The profile of norcocaine as a metabolite confirmed the involvement of norcocaine in cocaine's behavioral effects.