Characterization of dexloxiglumide in vitro biopharmaceutical properties and active transport

The objective of this work was to characterize dexloxiglumide biopharmaceutical properties in vitro and relate these characteristics to its in vivo absorption performance, and to assess dexloxiglumide interaction with P-glycoprotein (P-gp) and MRP1 to anticipate its drug interaction potential. Dexloxiglumide aqueous solubility was moderate and pH dependent. Dexloxiglumide exhibited moderate Caco-2 permeability that was polarized, concentration dependent, and pH dependent. The apical-to-basolateral (AP-BL) permeability at pH 5 [14.5 (+/-1.8) x 10(-6) cm/s] was 2-fold higher than at pH 7.5 [7.24 (+/-0.27) x 10(-6) cm/s]. Neutral and ionized dexloxiglumide species displayed permeabilities of 30.8 (+/-8.4) x 10(-6) cm/s and 9.03 (+/-1.31) x 10(-6) cm/s, respectively. The transport of dexloxiglumide across MDR1-MDCK (P-gp overexpressing Madine Darby canine kidney cells) monolayers was polarized, with a BL-AP/AP-BL permeability ratio of 9.35 (+/-0.73), which was reduced to 1.03 (+/-0.03) by P-gp inhibition. Rhodamine 123 efflux was reduced by dexloxiglumide from 4.06 (+/-0.34) to 2.84 (+/-0.15) across Caco-2 monolayers, and from 17.3 (+/-0.9) to 8.26 (+/-1.38) across MDR1-MDCK monolayers, further indicating dexloxiglumide interaction with P-gp. Additionally, P-gp ATPase activity increased with dexloxiglumide concentration. Dexloxiglumide was effluxed from MRP1-NIH3T3 cells (NIH-3T3 cells expressing the multidrug resistance-associated protein 1). Dexloxiglumide increased MRP1-substrate fluorescein uptake 4-fold, and fluorescein increased dexloxiglumide uptake 1.8-fold. Overall, in vitro transport studies indicate dexloxiglumide to be moderately soluble and moderately permeable, which is in agreement with the incomplete oral absorption of dexloxiglumide. In vitro, dexloxiglumide was moderately modulated by P-gp and MRP1, which provides a rationale for the design of drug interaction studies.