Intraluminal drug and formulation behavior and integration in in vitro permeability estimation:: A case study with amprenavir
Intraluminal drug and formulation behavior and integration in in vitro permeability estimation:: A case study with amprenavir
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DOI：
10.1002/jps.20553
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发表时间：
2006-02-01
影响因子：
3.8
通讯作者：
Augustijns, P
中科院分区：
文献类型：
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作者：
Brouwers, J;Tack, J;Augustijns, P
本研究的目的是评估生物相关顶端条件对 Caco-2 系统中安普那韦肠道通透性评估的影响，安普那韦是外排载体 P-糖蛋白 (P-gp) 的水溶性较差的底物。为了建立生物相关条件，在摄入安普那韦标准制剂（Agenerase（R））之前和之后4小时期间，从禁食受试者的十二指肠和空肠中吸出人肠液（HIF）。 HIF 样品的特征在于磷脂、单个胆汁盐、安普那韦和赋形剂 d-α-生育酚聚乙二醇 1000 琥珀酸酯 (TPGS) 的浓度；随后，将这些样品在 Caco-2 系统中在安普那韦渗透性评估过程中的使用与标准条件（安普那韦 10 μM 溶解在基于 HBSS 的传输介质中）进行比较。增溶赋形剂 TPGS 的存在导致腔内安普那韦浓度较高（mM 范围），并以浓度依赖性方式影响通透性。在观察到的管腔内 TPGS 浓度（mM 范围）下，TPGS 似乎完全抑制安普那韦和 P-gp 之间的相互作用，表明在临床环境中 P-gp 对安普那韦跨上皮转运的影响可能可以忽略不计。这项研究说明了药物摄入后评估管腔内条件及其在体外渗透性估计中的整合的重要性。 (C) 2005 Wiley-Liss, Inc. 和美国药剂师协会。
The purpose of this study was to assess the effect of biorelevant apical conditions on intestinal permeability estimation in the Caco-2 system for amprenavir, a poorly water-soluble substrate of the efflux carrier P-glycoprotein (P-gp). To establish biorelevant conditions, human intestinal fluids (HIF) were aspirated from the duodenum and jejunum in fasted subjects, before and during 4 h after the intake of a standard formulation of amprenavir (Agenerase(R)). The HIF samples were characterized with respect to the concentrations of phospholipids, individual bile salts, amprenavir, and the excipient d-alpha-tocopheryl polyethyleneglycol 1000 succinate (TPGS); subsequently, the use of these samples in the Caco-2 system during permeability estimation for amprenavir was compared to standard conditions (amprenavir 10 mu M dissolved in HBSS-based transport medium). The presence of the solubilizing excipient TPGS resulted in high intraluminal amprenavir concentrations (mM-range) and affected the permeability in a concentration-dependent way. At the observed intraluminal TPGS concentrations (mM-range), TPGS appeared to completely inhibit the interaction between amprenavir and P-gp, suggesting that the effect of P-gp on transepithelial transport of amprenavir in a clinical setting is probably negligible. This study illustrates the importance of the evaluation of intraluminal conditions after drug intake and their integration in permeability estimation in vitro. (C) 2005 Wiley-Liss, Inc. and the American Pharmacists Association.