Chen C, Pollack G M
Division of Drug Delivery and Disposition, School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
J Pharmacol Exp Ther. 1998 Nov;287(2):545-52.
This study was undertaken to test the hypothesis that P-glycoprotein (P-gp) modulates opioid peptide pharmacodynamics. [D-Penicillamine2, 5]enkephalin (DPDPE) (10 mg/kg i.v.) was administered to mdr1a(-/-) and wild-type mice to assess systemic disposition and antinociception. A subsequent dose-response experiment examined the impact of P-gp on DPDPE antinociception. In addition, the time course of antinociception was determined after a 0.9-mg/kg [mdr1a(-/-) mice] or 24-mg/kg (FVB mice) i.v. dose. Data were fit with a series of pharmacokinetic-pharmacodynamic models to compare the disposition and action of DPDPE in the two mouse strains. A 10-mg/kg dose produced >80% maximum possible response at all time points in mdr1a(-/-) mice; peak antinociception was <20% maximum possible response in FVB mice. DPDPE systemic disposition did not differ between the two mouse strains. Although brain tissue concentrations were 2- to 4-fold higher in mdr1a(-/-) compared to FVB mice, the dose required to elicit comparable antinociception was nearly 30-fold lower in mdr1a(-/-) mice; brain tissue EC50 differed by an order of magnitude in the two mouse strains. Pharmacokinetic-pharmacodynamic modeling indicated that the difference in antinociception between mdr1a(-/-) and FVB mice was a function of DPDPE distribution within brain, as well as between blood and brain, and not due to differences in intrinsic response. The results of this study suggest that DPDPE is a substrate of P-gp, and that P-gp is responsible, in part, for the low penetration of DPDPE into brain. The substantial difference in brain tissue EC50 in the absence vs. presence of P-gp suggests that P-gp modulates DPDPE-associated antinociception at sites other than the blood-brain interface.
本研究旨在验证P-糖蛋白（P-gp）调节阿片肽药效学这一假说。向mdr1a(-/-)小鼠和野生型小鼠静脉注射[D-青霉胺2,5]脑啡肽（DPDPE）（10 mg/kg），以评估其全身处置情况和镇痛作用。随后进行的剂量反应实验研究了P-gp对DPDPE镇痛作用的影响。此外，在静脉注射0.9 mg/kg（mdr1a(-/-)小鼠）或24 mg/kg（FVB小鼠）后，测定了镇痛作用的时间进程。数据采用一系列药代动力学-药效学模型进行拟合，以比较DPDPE在两种小鼠品系中的处置和作用情况。10 mg/kg的剂量在mdr1a(-/-)小鼠的所有时间点均产生了>80%的最大可能反应；FVB小鼠的镇痛峰值<20%的最大可能反应。两种小鼠品系之间DPDPE的全身处置情况无差异。尽管mdr1a(-/-)小鼠脑组织中的浓度比FVB小鼠高2至4倍，但在mdr1a(-/-)小鼠中引起相当镇痛作用所需的剂量几乎低30倍；两种小鼠品系的脑组织半数有效浓度（EC50）相差一个数量级。药代动力学-药效学模型表明，mdr1a(-/-)小鼠和FVB小鼠之间镇痛作用的差异是DPDPE在脑内以及血脑之间分布的函数，而非内在反应差异所致。本研究结果表明，DPDPE是P-gp的底物，且P-gp部分负责DPDPE进入脑内的低渗透率。在不存在与存在P-gp的情况下脑组织EC50的显著差异表明，P-gp在血脑界面以外的部位调节与DPDPE相关的镇痛作用。
