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Mechanisms of transport and structure-permeability relationship of sulfasalazine and its analogs in Caco-2 cell monolayers.

Abstract：

PURPOSE:To investigate the mechanisms involved in transport of sulfasalazine in Caco-2 cells. METHODS:Permeability coefficients of sulfasalazine and its analogs across Caco-2 cell monolayers were measured as a function of direction of transport, energy and concentration dependence, and in the presence of inhibitors of various cellular efflux pumps and transporters. RESULTS:Permeability coefficients of sulfasalazine across Caco-2 cell monolayers were approximately 342-, 261-, and 176-fold higher from basolateral to apical direction (BL-->AP) than from apical to basolateral direction (AP-->BL) at 100, 200, and 500 microM, respectively. Carrier permeability coefficient, non-saturable membrane permeability coefficient, and Michaelis constant were estimated to be 1.4x10(-5) cm/s, 1.9x10(-8) cm/s, and 369 microM, respectively. The efflux of sulfasalazine was completely blocked at 4 degrees C and in the presence of an uncoupler of oxidative phosphorylation. Using cellular efflux inhibitors, the permeability of sulfasalazine was shown to depend on multidrug resistance-associated protein and anion sensitive transport mechanisms. Structure-permeability studies showed that the affinity of sulfasalazine for the cellular efflux pumps and transporters in Caco-2 cells depended strongly on the carboxylic acid functional group. CONCLUSIONS:The permeability of sulfasalazine across Caco-2 cell monolayer is very low due to its strong interaction with multiple cellular efflux pumps and transporters. This may partially explain its low absorption in vivo.

journal_name

Pharm Res

journal_title

Pharmaceutical research

authors

Liang E,Proudfoot J,Yazdanian M

doi

10.1023/a:1026450326712

subject

Has Abstract

pub_date

2000-10-01 00:00:00

pages

1168-74

issue

10

eissn

0724-8741

issn

1573-904X

journal_volume

17

pub_type

杂志文章

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