title: Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline.
abstract: The effects of OATP1B1, OAT3, and MRP2 on the pharmacokinetics of eluxadoline, an oral, locally active, opioid receptor agonist/antagonist being developed for treatment of IBS-d were assessed in vivo. Coadministration of a single 200 mg dose of eluxadoline with cyclosporine, and probenecid increased eluxadoline systemic exposure [AUC(0-inf) ] by 4.4- and 1.4-fold, respectively, whereas peak exposure (Cmax ) increased 6.2-fold and 1.3-fold, respectively. Cyclosporine had little effect on renal clearance (CLren ) of eluxadoline whereas probenecid reduced CLren by nearly 50%. These study results suggested that sinusoidal OATP1B1-mediated hepatic uptake of eluxadoline (during first-pass and systemic extraction) plays a major role in its absorption and disposition, whereas OAT3-mediated basolateral uptake in the proximal renal tubules and MRP2-mediated canalicular and renal tubular apical efflux play only minor roles in its overall disposition. All treatments were safe and well tolerated.
authors.affiliation: Furiex Pharmaceuticals Inc., Morrisville, NC, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: Davenport
authors.forename: Paul
authors.initials: P
authors.lastname: Covington
authors.forename: Laura
authors.initials: L
authors.lastname: Bonifacio
authors.forename: Gail
authors.initials: G
authors.lastname: McIntyre
authors.forename: Jürgen
authors.initials: J
authors.lastname: Venitz
mesh_terms: D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D027381:Liver-Specific Organic Anion Transporter 1; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D010649:Phenylalanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011339:Probenecid / Q000494:pharmacology
chemical_list: D016572:Cyclosporine; D007093:Imidazoles; D027381:Liver-Specific Organic Anion Transporter 1; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D010649:Phenylalanine; D011339:Probenecid; C000715087:ABCC2 protein, human; C503999:SLCO1B1 protein, human; C114338:organic anion transport protein 3; C583636:eluxadoline
keywords: cyclosporine; drug interaction; eluxadoline; pharmacokinetics; probenecid