Pharmacokinetic-Pharmacodynamic Modeling of the Antinociceptive Effect of Buprenorphine and Fentanyl in Rats: Role of Receptor Equilibration Kinetics

Abstract

The objective of this investigation was to characterize the pharmacokinetic/pharmacodynamic correlation of buprenorphine and fentanyl for the antinociceptive effect in rats. Data on the time course of the antinociceptive effect following intravenous administration of buprenorphine or fentanyl was analyzed in conjunction with plasma concentrations by nonlinear mixedeffects analysis. For fentanyl, the pharmacokinetics was described on the basis of a two-compartment pharmacokinetic model. For buprenorphine, a three-compartment pharmacokinetic model best described the concentration time course. To explain time dependencies in pharmacodynamics of buprenorphine and fentanyl, a combined effect compartment/receptor binding model was applied. A log logistic probability distribution model is proposed to account for censored tail-flick latencies. The model converged, yielding precise estimates of the parameters characterizing hysteresis. The results show that onset and offset of the antinociceptive effect of both buprenorphine and fentanyl is mainly determined by biophase distribution. The k eo was 0.024 min Ϫ1 [95% confidence interval (CI): 0.018 -0.030 min Ϫ1 ] and 0.123 min Ϫ1 (95% CI: 0.095-0.151 min Ϫ1 ) for buprenorphine and fentanyl, respectively. On the other hand, part of the hysteresis in the buprenorphine pharmacodynamics could be explained by slow receptor association/dissociation kinetics. The k off was 0.073 min Ϫ1 (95% CI: 0.042-0.104 min Ϫ1 ) and k on was 0.023 ml/ng/min (95% CI: 0.013-0.033 ml/ng/min). Fentanyl binds instantaneously to the OP3 receptor because no reasonable values for k on and k off were obtained with the dynamical receptor model. In contrast to earlier reports in the literature, the findings of this study show that the rate-limiting step in the onset and offset of buprenorphine's antinociceptive effect is distribution to the brain.Buprenorphine is a semisynthetic opiate synthesized from the precursor thebaine. Several studies have revealed OP3 (-opioid) receptor agonistic binding capacity for buprenorphine. More specifically, a study conducted in the spinal dog classified buprenorphine as a partial agonist for the OP3 receptor (Martin et al., 1976). The OP3 receptor is of specific interest, given its role in the mediation of analgesia (Zhang and Pasternak, 1981;Lutfy et al., 2003). In principle, partial agonists only produce a submaximal response relative to full agonists which display full efficacy. However, the exact behavior of buprenorphine at the OP3 receptor in relation to its analgesic effect has not yet been unequivocally clarified. Data from animal studies suggest that buprenorphine-mediated analgesia might be governed by a bell-shaped doseresponse curve (Cowan et al., 1977a,b;Dum and Herz, 1981). At the lower dose range, a dose-dependent increase in analgesia is observed, whereas at intermediate doses, the response is diminished. At relatively high doses, evidence for an inverse dose-response relationship has been obtained in animals. However, the observed pharmacologica...

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