Human jejunal permeability of cyclosporin A: Influence of surfactants on P-glycoprotein efflux in Caco-2 cells

Yu Yuan Chiu, Kazutaka Higaki, Brien L. Neudeck, Jeffrey L. Barnett, Lynda S. Welage, Gordon L. Amidon

Research output: Contribution to journalArticle

93 Citations (Scopus)

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 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) × 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.

Original languageEnglish
Pages (from-to)749-756
Number of pages8
JournalPharmaceutical Research
Volume20
Issue number5
DOIs
Publication statusPublished - May 1 2003

Fingerprint

Caco-2 Cells
P-Glycoprotein
Surface-Active Agents
Cyclosporine
Permeability
Phenylalanine
Propranolol
Solubility
Dissolution
Pharmaceutical Preparations

Keywords

  • Biopharmaceutic classification system
  • Caco-2 cell culture
  • Cyclosporin A
  • Intestinal permeability
  • P-glycoprotein

ASJC Scopus subject areas

  • Chemistry(all)
  • Pharmaceutical Science
  • Pharmacology

Cite this

Human jejunal permeability of cyclosporin A : Influence of surfactants on P-glycoprotein efflux in Caco-2 cells. / Chiu, Yu Yuan; Higaki, Kazutaka; Neudeck, Brien L.; Barnett, Jeffrey L.; Welage, Lynda S.; Amidon, Gordon L.

In: Pharmaceutical Research, Vol. 20, No. 5, 01.05.2003, p. 749-756.

Research output: Contribution to journalArticle

Chiu, Yu Yuan ; Higaki, Kazutaka ; Neudeck, Brien L. ; Barnett, Jeffrey L. ; Welage, Lynda S. ; Amidon, Gordon L. / Human jejunal permeability of cyclosporin A : Influence of surfactants on P-glycoprotein efflux in Caco-2 cells. In: Pharmaceutical Research. 2003 ; Vol. 20, No. 5. pp. 749-756.
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