To date, little is known about the transporter-mediated drug-drug interaction (DDI) potential of evogliptin, a novel DPP-4 inhibitor. The objective of this study was to evaluate the DDI potential of evogliptin using various in vitro assays in transporter-expressing cell lines. After incubating evogliptin with cells overexpressing OAT1, OAT3, OCT2, OATP1B1 and OATP1B3, there was no notable cellular accumulation of evogliptin (fold accumulation, 0.41-1.86). In bidirectional transport assays using a Caco-2 cell monolayer, a high efflux ratio (ER, 522) of evogliptin was observed, which was significantly decreased (97.96%) in the presence of a potent P-gp inhibitor. In assays using MDCKII-BCRP cell monolayers, by contrast, a low net ER (1.16-1.26) was found. In similar cellular uptake and bidirectional studies with probe substrates of P-gp, BCRP, OAT1, OAT3, OCT2, OATP1B1 and OATP1B3, the active transport of the substrates was not significantly suppressed by evogliptin. These results suggest that evogliptin may be a substrate of P-gp, but not a substrate of BCRP, OAT1B1, OAT1B3, OAT1, OAT3 or OCT2, and not an inhibitor of any of these transporters. Therefore, it could be concluded that evogliptin has some DDI potential involving P-gp, but it has low potential of DDI mediated by the other transporters.

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(S)-2-Ethoxy-3-(4-{3-methyl-5-[4-(3-methyl-isoxazol-5-yl)-phenyl]thiophen-2-ylmethoxy}-phenyl)-propionic acid (PAM-1616) is a novel peroxisome proliferators-activated receptor γ (PPARγ) partial agonist with excellent antihyperglycemic activity. It is a promising new drug candidate for the treatment of type-2 diabetes with reduced possibility of edema in vitro/in vivo. In order to evaluate the pharmacokinetics of PAM-1616, a reliable, selective and sensitive highperformance liquid chromatography/electrospray ionization tandem mass spectrometry was developed for the quantification of PAM-1616 in rat plasma. The analytes were extracted from rat plasma with ethyl acetate, separated on an Atlantis dC(18) column with a mobile phase of 75% acetonitrile in 10 mM ammonium formate (pH 4.5), and detected by tandem mass spectrometry in the selective reaction monitoring mode. The calibration curve was linear (r (2) = 0.999) over the concentration range of 0.05-20.0 μg/mL and the lower limit of quantification was 0.05 μg/mL. The coefficient of variation and relative error at four QC levels were 1.8% to 14.3% and -10.0% to 6.5%, respectively. The present method was successfully applied to the pharmacokinetic study of PAM-1616 after intravenous administration of PAM-1616 potassium at a dose of 1 mg/kg in rats.