A pharmacokinetic-pharmacodynamic model of tolerance to morphine analgesia during infusion in rats
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A pharmacokinetic-pharmacodynamic (PK-PD) model was constructed to describe the kinetics of tolerance development to morphine-induced antinociception. Tail-flick latencies in response to hot water (50°C) were assessed in male Sprague-Dawley rats exposed to a 12-hr iv infusion of either morphine (1.4 to 3.0 mg/kg per hr) or saline. Morphine-induced antinociception, expressed as the percentage of maximum possible response (%MPR), peaked after 120 min of infusion and decreased thereafter despite sustained systemic morphine concentrations. Both the rate and extent of tolerance development increased with increasing concentrations; an overall residual effect of approximately 24% MPR was observed at the end of the infusion regardless of the steady-state morphine concentration. The kinetics of tolerance offset were examined in a separate experiment by assessing tail-flick latency 15 min after morphine iv bolus (2 mg/kg) in tolerant and control rats. Recovery of response neared completion 18.5 days after a 12-hr exposure to morphine (2.0 mg/kg per hr). A PK-PD model was constructed to account for the delay in onset of antinociceptive effect and tolerance development relative to the blood concentration-time profile. According to this model, both the extent and the rate of tolerance development were modulated by the kinetics of the drug in the central compartment. Accumulation of a hypothetical “inhibitor” acting either as a reverse agonist, a competitive or noncompetitive antagonist, or a partial agonist could potentially account for the loss of pharmacologic effect in the presence of an agonist. The rate of tolerance development predicted from the PK-PD model varied widely (28-fold) depending on the type of pharmacologic interaction selected to account for the loss of effect. Using the rate of tolerance offset to discriminate between the different models (t1/2 offset 5.4 days), onset and offset of tolerance was described accurately by postulating that the inhibitor behaves as a partial agonist with low intrinsic activity (5.5% MPR) and high binding affinity for the receptor (IC50 15.0 ng/ml).
Key Wordspharmacokinetic-pharmacodynamic model tolerance morphine antinociception analgesia opiates
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- 1.B. M. Cox. Drug tolerance and physical dependence. In W. B. Pratt and P. Taylor (eds.),Principles of Drug Action: The Basis of Pharmacology, 3rd ed., Churchill Livingstone, New York, 1990, pp. 639–690.Google Scholar
- 31.M. G»rdmark, M. Ekblom, R. Bouw, and M. Hammarlund-Udenaes. Quantification of effect delay and acute tolerance development to morphine in the rat.J. Pharmacol. Exp. Ther. 267:1061–1067 (1993).Google Scholar
- 35.M. R. Fennessy and J. R. Lee. The assessment of and the problems involved in the experimental evaluation of narcotic analgesics. In S. Ehrenpreis and A. Neidle (eds.),Methods in Narcotics Research, Marcel Dekker, New York, 1975, pp. 73–99.Google Scholar
- 46.L. K. Paalzow. Measurement and modeling of analgesic drug effect. In C. J. van Boxtel, N. H. G. Holford, and M. Danhof (eds.),The In Vivo Study of Drug Action, Elsevier, Amsterdam, The Netherlands, 1992, pp. 133–153.Google Scholar