Chen C, Pollack G M
Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina at Chapel Hill 27599-7360, USA.
Pharm Res. 1999 Feb;16(2):296-301. doi: 10.1023/a:1018892811980.
This study was conducted to examine the influence of P-glycoprotein (P-gp) modulation on the pharmacodynamics of the model opioid peptide DPDPE.
Mice (n = 5-7/group) were pretreated with a single oral dose of the P-gp inhibitor GF120918 (25 or 250 mg/kg) or vehicle. 3H-DPDPE (10 mg/kg) or saline was administered 2.5 hr after pretreatment. Antinociception was determined, and blood and brain tissue were obtained, 10 min after DPDPE administration.
A significant difference (p < 0.001) in DPDPE-associated antinociception was observed among mice pretreated with a 25- (83 +/- 16% MPR) or 250- (95 +/- 5% MPR) mg/kg dose of GF120918 in comparison to mice pretreated with vehicle (24 +/- 14% MPR) or mice receiving GF120918 without DPDPE (12 +/- 8% MPR). A significant difference (p < 0.01) in brain tissue DPDPE concentration also was observed among treatment groups [25 +/- 6 ng/g (vehicle), 37 +/- 11 ng/g (25 mg/kg GF120918), 70 +/- 8 ng/g (250 mg/kg GF120918)]. In contrast, blood DPDPE concentrations were not statistically different between groups (678 +/- 66, 677 +/- 130, and 818 +/- 236 ng/ml for vehicle, GF120918 [25 mg/kg], and GF120918 [250 mg/kg], respectively). A single 100-mg/kg i.p. dose of (+)verapamil increased the brain:blood DPDPE concentration ratio by approximately 70% relative to saline-treated control mice (0.139 +/- 0.021 vs. 0.0814 +/- 0.0130, p < 0.01), a change in partitioning similar to that observed with the low dose of GF120918. These data provide further support for a P-gp-based mechanism of brain:blood DPDPE distribution.
The present study demonstrates that GF120918 modulates blood-brain disposition and antinociception of DPDPE. Coadministration of a P-gp inhibitor with DPDPE may improve the pharmacologic activity of this opioid peptide.
本研究旨在探讨P-糖蛋白（P-gp）调节对模型阿片肽DPDPE药效学的影响。
小鼠（每组n = 5 - 7只）单次口服P-gp抑制剂GF120918（25或250 mg/kg）或赋形剂进行预处理。预处理后2.5小时给予3H-DPDPE（10 mg/kg）或生理盐水。给药后10分钟测定镇痛作用，并采集血液和脑组织。
与用赋形剂预处理的小鼠（24±14%最大可能效应，MPR）或未给予DPDPE而接受GF120918的小鼠（12±8% MPR）相比，用25（83±16% MPR）或250（95±5% MPR）mg/kg剂量的GF120918预处理的小鼠中，观察到与DPDPE相关的镇痛作用有显著差异（p < 0.001）。各治疗组之间脑组织中DPDPE浓度也有显著差异（赋形剂组为25±6 ng/g，25 mg/kg GF120918组为37±11 ng/g，250 mg/kg GF120918组为70±8 ng/g）（p < 0.01）。相比之下，各组之间血液中DPDPE浓度无统计学差异（赋形剂组、25 mg/kg GF120918组和250 mg/kg GF120918组分别为678±66、677±130和818±236 ng/ml）。腹腔注射单次100 mg/kg剂量的（+）维拉帕米使脑/血DPDPE浓度比相对于生理盐水处理的对照小鼠增加了约70%（0.139±0.021对0.0814±0.0130，p < 0.01），这种分布变化与低剂量GF120918观察到的相似。这些数据为基于P-gp的脑/血DPDPE分布机制提供了进一步支持。
本研究表明GF120918调节DPDPE的血脑分布和镇痛作用。P-gp抑制剂与DPDPE联合给药可能会改善这种阿片肽的药理活性。
