Ouellet D M, Pollack G M
Division of Pharmaceutics, School of Pharmacy, University of North Carolina at Chapel Hill 27599-7360, USA.
J Pharmacokinet Biopharm. 1995 Dec;23(6):531-49. doi: 10.1007/BF02353460.
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 degrees 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).
构建了一个药代动力学-药效学（PK-PD）模型，以描述对吗啡诱导的镇痛耐受性发展的动力学。在接受12小时静脉输注吗啡（1.4至3.0毫克/千克/小时）或生理盐水的雄性Sprague-Dawley大鼠中，评估对热水（50摄氏度）的甩尾潜伏期。吗啡诱导的镇痛作用，以最大可能反应百分比（%MPR）表示，在输注120分钟后达到峰值，此后尽管全身吗啡浓度持续存在，但仍有所下降。耐受性发展的速率和程度均随浓度增加而增加；无论稳态吗啡浓度如何，在输注结束时均观察到约24%MPR的总体残余效应。在一项单独的实验中，通过评估耐受性大鼠和对照大鼠静脉注射吗啡推注（2毫克/千克）15分钟后的甩尾潜伏期，研究了耐受性抵消的动力学。在暴露于吗啡（2.0毫克/千克/小时）12小时后，反应恢复接近完成，时间为18.5天。构建了一个PK-PD模型，以解释镇痛作用起效和耐受性发展相对于血药浓度-时间曲线的延迟。根据该模型，耐受性发展的程度和速率均受药物在中央室的动力学调节。一种假设的“抑制剂”的积累，其作用为反向激动剂、竞争性或非竞争性拮抗剂或部分激动剂，可能是在激动剂存在时药理效应丧失的原因。根据PK-PD模型预测的耐受性发展速率差异很大（28倍），具体取决于为解释效应丧失而选择的药理相互作用类型。通过假设抑制剂表现为具有低内在活性（5.5%MPR）和对受体高结合亲和力（IC50为15.0纳克/毫升）的部分激动剂，利用耐受性抵消速率来区分不同模型（t1/2抵消为5.4天），准确描述了耐受性的起效和抵消。
