Effect of uptake transporters OAT3 and OATP1B1 and efflux transporter MRP2 on the pharmacokinetics of eluxadoline

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.