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

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Abstract

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, Vss (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.

Introduction

Buprenorphine (BN) is an oripavine derivative that acts as a high affinity partial agonist at μ opioid receptors (Cowan et al., 1977a; Cowan, 1995). On the basis of encouraging clinical results, accumulated over two decades (e.g., Jasinski et al., 1978; Mello and Mendelson, 1980; Lange et al., 1990; Johnson et al., 1995; Greenwald et al., 1999), buprenorphine is now recognized as a safe and effective analgesic and, additionally, as a substance for the treatment of opioid dependence (Bickel and Amass, 1995), particularly in combination with naloxone, the standard narcotic antagonist (Amass et al., 2000). An enduring and intriguing property of BN is its bell-shaped dose–response curve in several rodent antinociceptive assays. Thus, BN is associated with antinociception at low doses yet higher doses are often less effective (Cowan et al., 1977a, Cowan et al., 1977b; Wheeler-Aceto and Cowan, 1991). With this in mind, we have studied the pharmacokinetics of BN and its major metabolite, norbuprenorphine (NBN), in rats with special reference to possible nonlinear pharmacokinetics.

The pharmacokinetics and disposition of BN and NBN in animals or humans have not been well characterized due to difficulties in the determination of their plasma levels. The assays used in earlier pharmacokinetic studies were either radio-immuno or enzyme-immuno methods. These methods were generally not specific and cross-activities from the metabolites were reported frequently. Ohtani’s group was the first to describe the pharmacokinetics of BN and NBN in rats (Ohtani et al., 1994, Ohtani et al., 1995, Ohtani et al., 1997) using a specific gas chromatographic–mass spectrometric (GC–MS) assay for BN and NBN. Their pharmacokinetic parameters could not be adapted readily to the present study for the following reasons: (a) the pharmacokinetics of BN and NBN were studied in separate groups of animals (Ohtani et al., 1995, Ohtani et al., 1997). (b) The antinociception (Ohtani et al., 1995) and respiratory depression (Ohtani et al., 1997) studies were of short duration (only 6 and 8 h post dosing). It is possible that systemic elimination, and duration of effect, could be longer when a higher dose of BN is administered. (c) The dose (0.008 mg/kg BN) in the antinociception study (Ohtani et al., 1995) was far below the reported dose ranges exhibiting the bell-shaped dose–response curve (Cowan, 1995).

The objective of the present study was to characterize, in a comprehensive manner, the pharmacokinetics of BN and NBN after different single intravenous doses of BN in rats.

Section snippets

Materials

Buprenorphine hydrochloride was provided by the National Institute on Drug Abuse (Bethesda, MD) and dissolved in normal saline to give concentrations of 1, 3 and 5 mg/ml (calculated as base), respectively. PE-50 tubing (0.58 mm i.d.) was purchased from Harvard Apparatus (Holliston, MA) and silastic tubing (0.51 mm i.d.) from VWR Scientific Products (Bridgeport, NJ).

Buprenorphine-D4 (internal standard) was purchased from Radian International (Austin, TX). Pentafluoropropionic anhydride was of

Results

Due to the extremely low plasma concentrations after 0.1 and 0.3 mg/kg of BN, the pharmacokinetic profiles of BN and NBN at these two doses could not be characterized completely.

Discussion

Preliminary studies indicated that plasma elimination half-lives would be about 4–5 h for both BN and NBN. Therefore, blood-sampling times were scheduled for up to 24 h post dosing (∼4–5 half-lives), that is, long enough to characterize in detail the pharmacokinetics and dispositions of BN and NBN. The doses of BN selected for this study (0.1, 0.3, 1, 3, 10, and 30 mg/kg) served as representative doses from the entire dose range reported to construct bell-shaped dose–response curves (Cowan et

Acknowledgements

The authors are grateful for the helpful suggestions of Ms. Gennet Tegegne of R.W. Johnson, PRI (Spring House, PA).

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