研究普朗尼克 P85 胶束对 P 糖蛋白抑制的胶束效应：细胞积累和平衡透析研究。
Investigation of the micellar effect of pluronic P85 on P-glycoprotein inhibition: cell accumulation and equilibrium dialysis studies.
机构信息
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 308 Harvard St. SE, Minneapolis, Minnesota 55455, USA.
出版信息
J Pharm Sci. 2009 Nov;98(11):4170-90. doi: 10.1002/jps.21723.
The objective of this study was: (1) to characterize the P-gp inhibitory effect of different concentrations of Pluronic P85 on anti-HIV-1 drug cellular accumulation, and (2) to investigate the relationship between cellular accumulation and free fraction of drug. Cellular accumulation studies in MDCKII-WT and MDCKII-MDR1 cell monolayers showed a biphasic dose response characterized by decline in accumulation at Pluronic concentrations greater than the CMC. This phenomenon was independent of the inhibition of P-gp efflux by Pluronic. Cell-free equilibrium dialysis was used to determine the effect of Pluronic P85 on drug free fraction and the affinity of Pluronic micelles for drug was modeled. Nelfinavir and saquinavir associated extensively with micelles and equilibrium free fractions were low at P85 concentrations above the CMC, with association constants being in the order nelfinavir > saquinavir >>> abacavir. Abacavir, a P-gp substrate, showed no association with micelles yet showed a biphasic response in cellular accumulation. These data suggest that, above the CMC, inhibition of P-gp is not affected but rather factors such as micellar trapping could contribute to decreased accumulation. Therefore, the in vitro evaluation of the effect of Pluronic formulations on active transport should take into account both the physicochemical properties of drug and the composition of Pluronic.
本研究的目的是
(1) 研究不同浓度的 Pluronic P85 对抗 HIV-1 药物细胞内蓄积的 P-糖蛋白抑制作用；(2) 研究细胞内蓄积与药物游离分数之间的关系。在 MDCKII-WT 和 MDCKII-MDR1 细胞单层中的细胞蓄积研究显示，蓄积呈双相剂量反应，特征是在高于 CMC 的 Pluronic 浓度下，蓄积下降。这种现象与 Pluronic 对 P-糖蛋白外排的抑制无关。采用无细胞平衡透析法测定 Pluronic P85 对药物游离分数的影响，并对 Pluronic 胶束与药物的亲和力进行了模型化。奈非那韦和沙奎那韦与胶束广泛结合，在高于 CMC 的 P85 浓度下，平衡游离分数较低，结合常数的顺序为奈非那韦>沙奎那韦>>阿巴卡韦。阿巴卡韦是 P-糖蛋白的底物，与胶束无结合，但在细胞蓄积中呈双相反应。这些数据表明，高于 CMC 时，P-糖蛋白的抑制不受影响，而是胶束捕获等因素可能导致蓄积减少。因此，应考虑药物的物理化学性质和 Pluronic 的组成，对 Pluronic 制剂对主动转运的影响进行体外评价。
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