Characterization of the pharmacokinetics of buprenorphine and norbuprenorphine in rats after intravenous bolus administration of buprenorphine.

The purpose of this project was to characterize the dose-dependent pharmacokinetics of buprenorphine (BN) and norbuprenorphine (NBN), the primary metabolite, after intravenous administration of different doses of BN to rats. Adult male Sprague-Dawley rats were divided into six groups and received a single intravenous bolus dose of 0.1, 0.3, 1, 3, 10 or 30 mg/kg of BN. A separate study was performed where BN and NBN were simultaneously administered intravenously (1 mg/kg+1 mg/kg). Plasma samples were obtained by centrifugation of the blood and analyzed for BN and NBN using a sensitive and selective gas chromatographic-mass spectrometric (GC-MS) bio-analytical method. Noncompartmental and compartmental methods were used to perform pharmacokinetic data analysis. BN declined triexponentially with a dose-dependent increase in its volume of distribution, V(ss) (8.37-18.2 l/kg) and clearance CL (2.70-6.10 l/h per kg). The pharmacokinetics of NBN were linear and biexponential. Coadministration of BN and NBN resulted in a significant increase in the volume of distribution and clearance of BN. The present results suggest that the nonlinear disposition in the clearance and volume of distribution of BN can be attributed, in part, to the increasing concentration of the metabolite.