Authors: Yassen, Ashraf¹; Olofsen, Erik²; Kan, Jingmin¹; Dahan, Albert²; Danhof, Meindert¹

Source: Clinical Pharmacokinetics, Volume 46, Number 5, 2007 , pp. 433-447(15)

Publisher: Adis International

Abstract:

Objectives: This investigation describes the interspecies scaling of the pharmacokinetics and pharmacodynamics of buprenorphine.

Methods: Data on the time course of the antinociceptive and respiratory depressant effects of buprenorphine in rats and in humans were simultaneously analysed on the basis of a mechanism-based pharmacokinetic-pharmacodynamic model.

Results: An allometric three-compartment pharmacokinetic model described the time course of the concentration in plasma. The value of the allometric coefficient for clearance was 35.2 mL/min (relative standard error [RSE] = 5.6%) and the value of the allometric exponent was 0.76 (RSE 5.61%). A combined biophase distribution-receptor association/dissociation model with a linear transduction function described hysteresis between plasma concentration and effect. The values of the drug-specific pharmacodynamic parameters were identical in rats and in humans. For the respiratory depressant effect, the values of the second-order rate constant of receptor association (k_on) and the first-order rate constant of receptor dissociation (k_off) were 0.23 mL/ng/min (RSE = 15.8%) and 0.014 min⁻¹ (RSE = 27.7%), respectively, and the value of the equilibrium dissociation constant (K_diss) was 0.13 nmol/L. The value of the intrinsic activity α was 0.52 (RSE = 3.4%). For the antinociceptive effect, the values of the k_on and k_off were 0.015 mL/ng/min (RSE = 18.3%) and 0.053 min⁻¹ (RSE = 23.1%), respectively. The value of the K_diss was 7.5 nmol/L. An allometric equation described the scaling of the system-specific parameter, the first-order distribution rate constant (k_e0). The value of the allometric coefficient for the k_e0 was 0.0303 min⁻¹ (RSE = 11.3%) and the value of the exponent was −0.28 (RSE = 9.6%).

Conclusions: The different values of the drug-specific pharmacodynamic parameters are consistent with the different opioid μ receptor subtypes involved in the antinociceptive and respiratory depressant effects.

Keywords: Buprenorphine; Buprenorphine; Pharmacodynamic modelling; Pharmacokinetic modelling

Document Type: Research article

Affiliations: 1: 1 Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Gorleaus Laboratories, Leiden, The Netherlands 2: 2 Division of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands

Publication date: 2007-01-01

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