The use of a dendrimer-propranolol prodrug to bypass efflux transporters and enhance oral bioavailability
The use of a dendrimer-propranolol prodrug to bypass efflux transporters and enhance oral bioavailability
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DOI：
10.1016/j.jconrel.2003.12.006
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发表时间：
2004-03-24
影响因子：
10.8
通讯作者：
Attwood, D
中科院分区：
文献类型：
--
作者：
D'Emanuele, A;Jevprasesphant, R;Attwood, D
本研究的目的是确定通过与第 3 代 (G3) 和月桂酰基-G3 PAMAM 树枝状聚合物缀合形成前药对普萘洛尔跨人结肠腺癌细胞系 Caco-2 单层转运的影响。普萘洛尔是一种难溶性药物，已知是 P-糖蛋白 (P-gp) 外排转运蛋白的底物。普萘洛尔-G3 树枝状聚合物缀合物通过两个、四个或六个普萘洛尔分子的表面附着来合成。与 G3 树枝状聚合物缀合后，普萘洛尔的顶端 (A) 至基底外侧 (B) 表观渗透系数 P-app 增加，而其 B --> A P-app 降低。普萘洛尔与月桂酰-G3 树枝状聚合物的缀合进一步增加了其 A --> B P-app。我们的研究结果表明，在内吞作用抑制剂秋水仙碱存在下，普萘洛尔缀合物的 A --> B P-app 降低，并且在 4°C 时低于 37°C，表明增强机制涉及内吞作用介导的跨上皮转运。在 P-gp 抑制剂环孢菌素 A 存在的情况下，缀合的普萘洛尔的 A --> B P-app 没有改变，这表明药物与树枝状聚合物的缀合可以绕过外排转运蛋白。结果表明，树枝状药物前药可用于增加药物溶解度并绕过药物外排转运蛋白，从而提高药物生物利用度。 (C) 2004 Elsevier B.V. 保留所有权利。
The aim of the study was to determine the effects on the transport of propranolol across monolayers of the human colon adenocarcinoma cell line, Caco-2, of forming a prodrug by conjugating to generation 3 (G3) and lauroyl-G3 PAMAM dendrimers. Propranolol is a poorly soluble drug known substrate of the P-glycoprotein (P-gp) efflux transporter. Propranolol-G3 dendrimer conjugates were synthesised by surface attachment of two, four or six propranolol molecules. The apical (A) to basolateral (B) apparent permeability coefficient, P-app, of propranolol was increased and its B --> A P-app decreased following conjugation to G3 dendrimers. Conjugation of propranolol to lauroyl-G3 dendrimers further increased its A --> B P-app. Our findings show that the A --> B P-app of propranolol conjugates was reduced in the presence of the endocytosis inhibitor colchicine and was lower at 4 C than at 37 C, suggesting that the enhancement mechanism involves endocytosis-mediated transepithelial transport. The A --> B P-app of conjugated propranolol was not altered in the presence of the P-gp inhibitor cyclosporin A suggesting that conjugation of drug to dendrimer allows the bypassing of the efflux transporter. The results suggest that dendrimer-drug prodrugs may be used to increase drug solubility and bypass drug efflux transporters, therefore increasing drug bioavailability. (C) 2004 Elsevier B.V. All rights reserved.