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 language | English |
|---|---|
| Pages (from-to) | 749-756 |
| Number of pages | 8 |
| Journal | Pharmaceutical Research |
| Volume | 20 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 1 2003 |
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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 journal › Article
}
TY - JOUR
T1 - Human jejunal permeability of cyclosporin A
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.
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
KW - Cyclosporin A
KW - Intestinal permeability
KW - P-glycoprotein
UR - http://www.scopus.com/inward/record.url?scp=0037407282&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037407282&partnerID=8YFLogxK
U2 - 10.1023/A:1023481418576
DO - 10.1023/A:1023481418576
M3 - Article
C2 - 12751630
AN - SCOPUS:0037407282
VL - 20
SP - 749
EP - 756
JO - Pharmaceutical Research
JF - Pharmaceutical Research
SN - 0724-8741
IS - 5
ER -