期刊
PHARMACEUTICAL RESEARCH
卷 20, 期 5, 页码 749-756出版社
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1023/A:1023481418576
关键词
intestinal permeability; P-glycoprotein; cyclosporin A; biopharmaceutic classification system; Caco-2 cell culture
资金
- NIGMS NIH HHS [R01-GM37188] Funding Source: Medline
Purpose. 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. Methods. 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. Results. The mean P-eff (+/-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. Conclusions. 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(R) oral formulations is the result of poor dissolution characteristics.
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