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.
Chiu
Yu-Yuan
YY
College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109, USA.
Higaki
Kazutaka
K
Neudeck
Brien L
BL
Barnett
Jeffrey L
JL
Welage
Lynda S
LS
Amidon
Gordon L
GL
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