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Human Jejunal Permeability of Cyclosporin A: Influence of Surfactants on P-Glycoprotein Efflux in Caco-2 Cells

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Abstract

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) × 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® oral formulations is the result of poor dissolution characteristics.

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Authors and Affiliations

  1. College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan, 48109

    Yu-Yuan Chiu, Kazutaka Higaki, Brien L. Neudeck, Lynda S. Welage & Gordon L. Amidon

  2. Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University, Okayama, 700-8350, Japan

    Kazutaka Higaki

  3. Pharmacy Services, University Hospitals, University of Michigan, Ann Arbor, Michigan, 48109

    Brien L. Neudeck & Lynda S. Welage

  4. Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical Center, Ann Arbor, Michigan, 48109

    Jeffrey L. Barnett

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  1. Yu-Yuan Chiu
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  2. Kazutaka Higaki
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Correspondence to Gordon L. Amidon.

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Chiu, YY., Higaki, K., Neudeck, B.L. et al. Human Jejunal Permeability of Cyclosporin A: Influence of Surfactants on P-Glycoprotein Efflux in Caco-2 Cells. Pharm Res 20, 749–756 (2003). https://doi.org/10.1023/A:1023481418576

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