Chiu Yu-Yuan, Higaki Kazutaka, Neudeck Brien L, Barnett Jeffrey L, Welage Lynda S, Amidon Gordon L
College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109, USA.
Pharm Res. 2003 May;20(5):749-56. doi: 10.1023/a:1023481418576.
The purpose of this work was to determine the jejunal permeability of cyclosporin A (CsA) in humans and whether formulation variables modulate the effects of P-glycoprotein (P-gp) on the permeability of CsA in Caco-2 cells.
A solution containing CsA, phenylalanine, propranolol, polyethyleneglycol (PEG) 400, and PEG 4000 was perfused through a 10-cm jejunal segment in 12 subjects. Caco-2 transport studies were performed using previously reported methodology.
The mean Peff (+/- SD) of CsA in humans was 1.65 (0.53). The mean permeabilities for phenylalanine, propranolol, and PEG 400 were 4.54 (2.39), 2.90 (1.28), and 0.83 (0.51) x 10(-4) cm/s, respectively. The presence of surfactants significantly decreased the permeabilities of CsA in both directions in Caco-2 cells.
The results suggest that the effects of surfactants via micellar solubilization and inhibition of P-gp efflux on CsA transport in Caco-2 cells are significant. CsA can rightly be classified as a low solubility-high permeability Class II BCS drug and its highly variable absorption from Sandimmune oral formulations is the result of poor dissolution characteristics.
本研究旨在确定环孢素A（CsA）在人体空肠的通透性，以及制剂变量是否会调节P-糖蛋白（P-gp）对Caco-2细胞中CsA通透性的影响。
将含有CsA、苯丙氨酸、普萘洛尔、聚乙二醇（PEG）400和PEG 4000的溶液灌注通过12名受试者的10厘米空肠段。使用先前报道的方法进行Caco-2转运研究。
CsA在人体中的平均有效渗透率（Peff，±标准差）为1.65（0.53）。苯丙氨酸、普萘洛尔和PEG 400的平均渗透率分别为4.54（2.39）、2.90（1.28）和0.83（0.51）×10⁻⁴厘米/秒。表面活性剂的存在显著降低了CsA在Caco-2细胞中双向的渗透率。
结果表明，表面活性剂通过胶束增溶和抑制P-gp外排对Caco-2细胞中CsA转运的影响显著。CsA可正确归类为低溶解性-高渗透性的II类BCS药物，其从山地明口服制剂中的吸收高度可变是溶解特性差的结果。
