In vitro evaluation of potential transporter‐mediated drug interactions of evogliptin

Abstract

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.

Pharmacokinetics and safety of evogliptin in hepatically impaired patients

“…Similar to the findings in our study, the 1.4–1.5‐fold increase in the exposure of patients with moderate hepatic impairment to evogliptin, when renal function is preserved, seems to be within a reasonable range. In addition, evogliptin is also a substrate of P‐glycoprotein (P‐gp) and the expression of P‐gp is known to be increased in patients who have liver diseases such as hepatitis C, hepatocellular carcinoma, HIV infection, NASH and cirrhosis 22–31 . However, we have not investigated the potential impact of changes in P‐gp expression on the disposition in the evogliptin in the current study.…”

“…In addition, evogliptin is also a substrate of P-glycoprotein (P-gp) and the expression of P-gp is known to be increased in patients who have liver diseases such as hepatitis C, hepatocellular carcinoma, HIV infection, NASH and cirrhosis. [22][23][24][25][26][27][28][29][30][31] However, we have not investigated the potential impact of changes in P-gp expression on the disposition in the evogliptin in the current study.…”

In-vitro and in situ assessment of the efflux of five antidepressants by breast cancer resistance protein

“…The cells for bidirectional transport studies were maintained and prepared using a previously published method . The cells were seeded on the apical side of transwell plates (Corning/Costar 3412 Polycarbonate Membrane Transwell Inserts, surface area, 4.6 cm 2 per well; pore size, 0.4 μm) with a cell density of 3.0 × 10 5 cells per well.…”

Effect of haemodialysis on the pharmacokinetics and pharmacodynamics of evogliptin

“…14 Interactions with other drugs metabolized by CYP enzymes are unlikely, making it a suitable option for patients who need to take multiple drugs. 15 Diabetic nephropathy, one of the most frequent and dangerous complications of type 2 DM, is the leading cause of CKD and subsequent ESRD, and renal replacement therapy such as haemodialysis (HD) is eventually needed. 16 Some experimental and clinical results suggest that the use of DPP-4 inhibitors may have significant beneficial pleiotropic effects on the progression of CKD.…”