title: Characterization of dexloxiglumide in vitro biopharmaceutical properties and active transport.
abstract: 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.
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D004285:Dogs; D004347:Drug Interactions; D019450:Genes, MDR; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D010421:Pentanoic Acids / Q000493:pharmacokinetics*; D010539:Permeability; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors*; D012995:Solubility
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000251:Adenosine Triphosphatases; D027501:Monocarboxylic Acid Transporters; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010421:Pentanoic Acids; D011949:Receptors, Cholecystokinin; C103490:dexloxiglumide; C421109:multidrug resistance-associated protein 1