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

doi:10.1023/A:1023481418576

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

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105 Scopus citations

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.

Original language	English (US)
Pages (from-to)	749-756
Number of pages	8
Journal	Pharmaceutical research
Volume	20
Issue number	5
DOIs	https://doi.org/10.1023/A:1023481418576
State	Published - May 1 2003

Bibliographical note

Funding Information:
This work was supported by NIH grant R01-GM37188. We thank the nurses at the General Clinical Research Center and the staff of the Gastrointestinal Physiology Laboratory, at the University of Michigan Medical Center for their support and assistance with this project. We also thank John Wlodyga for his valuable assistance in various phases of this study.

Keywords

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

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

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{\textregistered} oral formulations is the result of poor dissolution characteristics.",

keywords = "Biopharmaceutic classification system, Caco-2 cell culture, Cyclosporin A, Intestinal permeability, P-glycoprotein",

author = "Chiu, {Yu Yuan} and Kazutaka Higaki and Neudeck, {Brien L.} and Barnett, {Jeffrey L.} and Welage, {Lynda S.} and Amidon, {Gordon L.}",

note = "Funding Information: This work was supported by NIH grant R01-GM37188. We thank the nurses at the General Clinical Research Center and the staff of the Gastrointestinal Physiology Laboratory, at the University of Michigan Medical Center for their support and assistance with this project. We also thank John Wlodyga for his valuable assistance in various phases of this study.",

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T2 - Influence of surfactants on P-glycoprotein efflux in Caco-2 cells

AU - Chiu, Yu Yuan

AU - Higaki, Kazutaka

AU - Neudeck, Brien L.

AU - Barnett, Jeffrey L.

AU - Welage, Lynda S.

AU - Amidon, Gordon L.

N1 - Funding Information: This work was supported by NIH grant R01-GM37188. We thank the nurses at the General Clinical Research Center and the staff of the Gastrointestinal Physiology Laboratory, at the University of Michigan Medical Center for their support and assistance with this project. We also thank John Wlodyga for his valuable assistance in various phases of this study.

PY - 2003/5/1

Y1 - 2003/5/1

N2 - 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.

AB - 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.

KW - Biopharmaceutic classification system

KW - Caco-2 cell culture

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KW - Intestinal permeability

KW - P-glycoprotein

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

Abstract

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