Simulating kinetic parameters in transporter mediated permeability across Caco-2 cells. A case study of estrone-3-sulfate

Substances that compete for the same saturable intestinal transporters may when dosed together lead to altered permeability and hence influence bioavailability. The aim was to simulate kinetic parameters, i.e. Km and Jmax, for transporter mediated E1S permeability across Caco-2 cells by a combined experimental modeling approach. 4 classes of transporters were suggested to be involved in the permeability of E1S, i.e. apical influx (TI) and efflux (TIII) as well as basolateral efflux (TII) and influx (TIV). Efflux ratio of E1S was determined to 6.8. E1S is suggested to have highest affinity to TIII. TIV is however suggested to be rate limiting in exsorptive PAPP due to lower Jmax of TIV, compared to TIII. Possible interactions between E1S and the excipients erythrosine and Brij35 on these 4 classes of transporters were also studied. From these studies it is suggested that erythrosine does interact with E1S on apical efflux transporter TIII by competitive inhibition. Furthermore interaction between erythrosine and E1S is suggested on apical influx transporter (TI). Brij35 does not seem to interact with E1S on apical transporters. The present model seem to be a valuable tool to simulate kinetic parameters for compounds being substrates to multiple transporters as well as to estimate kinetic parameters for compounds interacting on the same transporters.

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