title: Sulfasalazine transport in in-vitro, ex-vivo and in-vivo absorption models: contribution of efflux carriers and their modulation by co-administration of synthetic nature-identical fruit extracts.
abstract: Sulfasalazine is characterised by low oral bioavailability. In this study, its intestinal transport characteristics were studied in an in-vitro, ex-vivo and in-situ system. The absorptive transport of sulfasalazine across Caco-2 monolayers appeared to be lower than the secretory transport (P(app-abs) = 0.21 +/- 0.02 x 10(-6) cm s(-1) and P(app-secr) = 2.97 +/- 0.30 x 10(-6) cm s(-1), respectively). This polarity in transport of sulfasalazine was not mediated by P-glycoprotein (P-gp), as inclusion of verapamil (100 microM) did not have any effect on the transport polarity of sulfasalazine. However, inclusion of the multidrug resistance-associated protein (MRP) inhibitors benzbromarone (50 microM) and sulfinpyrazone (1 mM), and the glutathione-depleting agent chlorodinitrobenzene (100 microM), resulted in an increased absorptive transport of sulfasalazine in the Caco-2 system (P(app-abs) = 0.64 +/- 0.02, 0.51 +/- 0.04 and 0.60 +/- 0.03 x 10(-6) cm s(-1), respectively). The interference of carriers implies that, during absorption, interactions with food components may occur at the level of this carrier. Therefore, the effect of food extracts was studied in a parallel set of experiments. For two standardized nature-identical fruit extracts (pineapple and apricot extract) a concentration-dependent absorption-enhancing effect could be observed in the Caco-2 system. The functional expression of similar carriers was also demonstrated in rat ileum in the Ussing chamber system. Interaction studies with fruit extracts in the Ussing chamber system, as well as in the in-situ intestinal perfusion study, revealed a 2- to 4-fold increase in the absorptive transport of sulfasalazine. These results indicate that food components in the intestinal lumen can have a significant impact on the intestinal absorption characteristics of sulfasalazine by modulating the biochemical barrier function of the intestinal mucosa.
authors.affiliation: Laboratory for Pharmacotechnology and Biopharmacy, Herestraat 49, Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Raf
authors.initials: R
authors.lastname: Mols
authors.forename: Sven
authors.initials: S
authors.lastname: Deferme
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
mesh_terms: D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D002851:Chromatography, High Pressure Liquid; D005638:Fruit / Q000737:chemistry*; D006801:Humans; D007408:Intestinal Absorption; D008954:Models, Biological; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors; D010936:Plant Extracts / Q000008:administration & dosage*; D051381:Rats; D012460:Sulfasalazine / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010936:Plant Extracts; D012460:Sulfasalazine