Human jejunal permeability of cyclosporin A: influence of surfactants on P-glycoprotein efflux in Caco-2 cells.
OBJECTIVE
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) 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 oral formulations is the result of poor dissolution characteristics.
College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109, USA.
Yu-Yuan
YY
Chiu
Kazutaka
K
Higaki
Brien L
BL
Neudeck
Jeffrey L
JL
Barnett
Lynda S
LS
Welage
Gordon L
GL
Amidon
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000328:Adult; D018938:Caco-2 Cells; D016572:Cyclosporine / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism*; D013501:Surface-Active Agents / Q000493:pharmacokinetics* / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D013501:Surface-Active Agents; D016572:Cyclosporine