Zheng Yi, Benet Leslie Z, Okochi Hideaki, Chen Xijing
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, #24 Tongjiaxiang, Mailbox 210, Nanjing, 210009, Jiangsu, China.
Pharm Res. 2015 Aug;32(8):2516-26. doi: 10.1007/s11095-015-1640-3. Epub 2015 Feb 19.
Recent controversial publications, citing studies purporting to show that P-gp mediates the transport of propranolol, proposed that passive biological membrane transport is negligible. Based on the BDDCS, the extensively metabolized-highly permeable-highly soluble BDDCS class 1 drug, propranolol, shows a high passive permeability at concentrations unrestricted by solubility that can overwhelm any potential transporter effects. Here we reinvestigate the effects of passive diffusion and carrier-mediated transport on S-propranolol.
Bidirectional permeability and inhibition of efflux transport studies were carried out in MDCK, MDCK-MDR1 and Caco-2 cell lines at different concentrations. Transcellular permeability studies were conducted at different apical pHs in the rat jejunum Ussing chamber model and PAMPA system.
S-propranolol exhibited efflux ratios lower than 1 in MDCK, MDCK-MDR1 and Caco-2 cells. No significant differences of Papp, B->A in the presence and absence of the efflux inhibitor GG918 were observed. However, an efflux ratio of 3.63 was found at apical pH 6.5 with significant decrease in Papp, A->B and increase in Papp, B->A compared to apical pH 7.4 in Caco-2 cell lines. The pH dependent permeability was confirmed in the Ussing chamber model. S-propranolol flux was unchanged during inhibition by verapamil and rifampin. Furthermore, pH dependent permeability was also observed in the PAMPA system.
S-propranolol does not exhibit active transport as proposed previously. The "false" positive efflux ratio can be explained by the pH partition theory. As expected, passive diffusion, but not active transport, plays the primary role in the permeability of the BDDCS class 1 drug propranolol.
近期有一些存在争议的出版物，引用了一些声称表明P-糖蛋白介导普萘洛尔转运的研究，提出被动生物膜转运可忽略不计。基于生物药剂学分类系统（BDDCS），广泛代谢-高渗透性-高溶解性的BDDCS 1类药物普萘洛尔，在不受溶解度限制的浓度下显示出高被动渗透性，这可能会掩盖任何潜在的转运体效应。在此，我们重新研究被动扩散和载体介导的转运对S-普萘洛尔的影响。
在不同浓度下，对MDCK、MDCK-MDR1和Caco-2细胞系进行双向渗透性和外排转运抑制研究。在大鼠空肠Ussing腔模型和PAMPA系统中，于不同顶端pH值下进行跨细胞渗透性研究。
在MDCK、MDCK-MDR1和Caco-2细胞中，S-普萘洛尔的外排率低于1。在存在和不存在外排抑制剂GG918的情况下，未观察到Papp，B->A有显著差异。然而，在Caco-2细胞系中，顶端pH值为6.5时外排率为3.63，与顶端pH值7.4相比，Papp，A->B显著降低，Papp，B->A增加。在Ussing腔模型中证实了pH依赖性渗透性。维拉帕米和利福平抑制期间，S-普萘洛尔通量未改变。此外，在PAMPA系统中也观察到了pH依赖性渗透性。
S-普萘洛尔并未如先前提出的那样表现出主动转运。“假”阳性外排率可用pH分配理论来解释。正如预期的那样，被动扩散而非主动转运在BDDCS 1类药物普萘洛尔的渗透性中起主要作用。
