Pharmacokinetics and pharmacodynamics of seven opioids in P-glycoprotein-competent mice:: Assessment of unbound brain EC50,u and correlation of in vitro, preclinical, and clinical data
Pharmacokinetics and pharmacodynamics of seven opioids in P-glycoprotein-competent mice:: Assessment of unbound brain EC50,u and correlation of in vitro, preclinical, and clinical data
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DOI：
10.1124/jpet.107.119560
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发表时间：
2007-10-01
影响因子：
3.5
通讯作者：
Pollack, Gary M.
中科院分区：
文献类型：
--
作者：
Kalvass, J. Cory;Olson, Emily R.;Pollack, Gary M.
进行本研究以评估未结合脑EC 50（EC 50，u）作为中枢活性药物体内效力的量度的效用。选择七种μ-阿片激动剂（阿芬太尼、芬太尼、洛哌丁胺、美沙酮、哌替啶、吗啡和舒芬太尼）作为模型中枢神经系统药物，因为它们引起容易测量的中枢作用（抗伤害感受）并且它们的临床药代动力学/药效学被充分理解。小鼠接受等效皮下剂量的一种模型阿片样物质。测定抗伤害感受的时间过程以及血清和脑浓度。使用药代动力学/药效学模型估计相关参数。获得阿片样物质结合亲和力（Ki）和功能活性[激动剂刺激的鸟苷5 '-O-（3-[S-35]硫代）三磷酸结合的EC 50]和相关临床参数的体外测量，以构建体外-临床前和临床前-临床相关性。在Ki和未结合脑EC 50，u之间观察到最强的体外与体内相关性（r（2）类似于0.8）。观察到小鼠血清和人血浆EC 50之间存在强相关性（r（2）= 0.949）;校正蛋白结合率后，相关性得到改善（r（2）= 0.995）。临床等效静脉注射剂量与Ki仅中度相关。然而，ED 50和EC 50（总血清、未结合血清、总脑和未结合脑）的估计值是临床等效静脉给药剂量的显著预测因子;观察到脑EC 50，u的相关性最好（r（2）= 0.982）。对于每种阿片类药物，小鼠脑平衡半衰期与临床测量的血浆效应部位平衡半衰期几乎相同。这些结果表明，小鼠是阿片类药物人脑处置和临床药理学的良好模型，并且可以使用相关未结合浓度实现体外与临床前和临床前与临床的上级相关性。
This study was conducted to assess the utility of unbound brain EC50 (EC50,u) as a measure of in vivo potency for centrally active drugs. Seven mu-opioid agonists (alfentanil, fentanyl, loperamide, methadone, meperidine, morphine, and sufentanil) were selected as model central nervous system drugs because they elicit a readily measurable central effect (antinociception) and their clinical pharmacokinetics/pharmacodynamics are well understood. Mice received an equipotent subcutaneous dose of one of the model opioids. The time course of antinociception and the serum and brain concentrations were determined. A pharmacokinetic/pharmacodynamic model was used to estimate relevant parameters. In vitro measures of opioid binding affinity (K-i) and functional activity [EC50 for agonist stimulated guanosine 5 '-O-(3-[S-35] thio) triphosphate binding] and relevant clinical parameters were obtained to construct in vitro-to-preclinical and preclinical-to-clinical correlations. The strongest in vitro-to-in vivo correlation was observed between K-i and unbound brain EC50,u (r(2) similar to 0.8). A strong correlation between mouse serum and human plasma EC50 was observed (r(2) = 0.949); the correlation was improved when corrected for protein binding (r(2) = 0.995). Clinical equipotent i.v. dose was only moderately related to Ki. However, estimates of ED50 and EC50 (total serum, unbound serum, total brain, and unbound brain) were significant predictors of clinical equipotent i.v. dose; the best correlation was observed for brain EC50,u (r(2) = 0.982). For each opioid, brain equilibration half-life in mice was almost identical to the plasma effect-site equilibration half-life measured clinically. These results indicate that the mouse is a good model for opioid human brain disposition and clinical pharmacology and that superior in vitro-to-preclinical and preclinicalto-clinical correlations can be achieved with relevant unbound concentrations.