Comparative Pharmacokinetics and Pharmacodynamics of a Novel Sodium-Glucose Cotransporter 2 Inhibitor, DWP16001, with Dapagliflozin and Ipragliflozin.

Min-Koo Choi,Mi Jie Park,Hye-Young Ji,Im-Sook Song,Ji-Soo Choi,So Jeong Nam

doi:10.3390/pharmaceutics12030268

Min-Koo Choi, Mi Jie Park + Show 4 more

Open Access

https://doi.org/10.3390/pharmaceutics12030268

Copy DOI

Abstract

Since sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced blood glucose level by inhibiting renal tubular glucose reabsorption mediated by SGLT2, we aimed to investigate the pharmacokinetics and kidney distribution of DWP16001, a novel SGLT2 inhibitor, and to compare these properties with those of dapagliflozin and ipragliflozin, representative SGLT2 inhibitors. The plasma exposure of DWP16001 was comparable with that of ipragliflozin but higher than that of dapagliflozin. DWP16001 showed the highest kidney distribution among three SGLT2 inhibitors when expressed as an area under curve (AUC) ratio of kidney to plasma (85.0 ± 16.1 for DWP16001, 64.6 ± 31.8 for dapagliflozin and 38.4 ± 5.3 for ipragliflozin). The organic anion transporter-mediated kidney uptake of DWP16001 could be partly attributed to the highest kidney uptake. Additionally, DWP16001 had the lowest half-maximal inhibitory concentration (IC50) to SGLT2, a target transporter (0.8 ± 0.3 nM for DWP16001, 1.6 ± 0.3 nM for dapagliflozin, and 8.9 ± 1.7 nM for ipragliflozin). The inhibition mode of DWP16001 on SGLT2 was reversible and competitive, but the recovery of the SGLT2 inhibition after the removal of SGLT2 inhibitors in CHO cells overexpressing SGLT2 was retained with DWP16001, which is not the case with dapagliflozin and ipragliflozin. In conclusion, selective and competitive SGLT2 inhibition of DWP16001 could potentiate the efficacy of DWP16001 in coordination with the higher kidney distribution and retained SGLT2 inhibition of DWP16001 relative to dapagliflozin and ipragliflozin.

Highlights

Achieving appropriate glycemic control for type 2 diabetes patients is a prerequisite for preventing cardiovascular and microvascular complications, and this can be guided by a combination of antidiabetic drugs with different modes of action [1].Sodium-glucose cotransporter 2 (SGLT2) inhibitors are the latest class of antidiabetic drugs that act through the inhibition of renal tubular glucose reabsorption and a reduction of blood glucose levels without stimulating insulin release [2]
Representative multiple reaction-monitoring (MRM) chromatograms of DWP16001, D4-DWP16001 (IS), dapagliflozin, and ipragliflozin (Figure 3) showed that all the analyte peaks obtained using the liquid-liquid extraction method using methyl tert-butyl ether (MTBE) were well separated with no interfering peaks at their respective retention times
Representative multiple reaction-monitoring (MRM) chromatograms of DWP16001, D4-DWP16001 (IS), dapagliflozin, and ipragliflozin (Figure 3) showed that all the analyte peaks oinbt(FiFteDpaiirggrif)nauueigeprrrleiderinfal22ggou..lzipPsiflinPrenoo.arzgdokidunstuc.hatctetiotihnloienqsiuprseiprdceet-srclaptirqeaoucftiodi(fvAe()eArxD)etWrtDeaPW nc1ttiPi6oo01nn0610t,m0im1(Be, et)(hsBD.o)4d-DD4uW-sDiPnW1g6P01M0610T(0IB1SE)(,IS(wC),)e(rdCea)pwdagaepllilaflgoslzeiflipnoa,zraiannt,deda(nDdw) ith no Representative multiple reaction-monitoring (MRM) chromatograms of DWP16001, D4-DWP16001 (IS), dapagliflozin, and ipragliflozin (Figure 3) showed that all the analyte peaks obtained using the liquid-liquid extraction method using MTBE were well separated with no interfering peaks at their respective retention times

Summary

Introduction

Achieving appropriate glycemic control for type 2 diabetes patients is a prerequisite for preventing cardiovascular and microvascular complications, and this can be guided by a combination of antidiabetic drugs with different modes of action [1]. Several SGLT2 inhibitors have been approved for the treatment of type 2 diabetes, including canagliflozin (Invokana®), dapagliflozin (Farxiga®), empagliflozin (Jardiance®), ipragliflozin (Suglat®), and tofogliflozin (Apleway®) [3,5]. T(hSet.dLroieudise, xMtrOac, tUwSAas).r[e1c4oCn]sMtietuthteydl-αin-D1-5g0luμcLopoyf rmanoobsiliedeph(AasMe,Ga)n(d29a03mμCLi/amlimquool)t wofatshpeurrecchoanssetditufreonmt was injected into a liquid chromatography–tandem mass spectrometry (LC–MS/MS) system. Pharmacokinetic parameters, such as the area under plasma concentration-time curve from zero to infinity (AUC), were calculated from plasma concentration vs time curves using non-compartment analysis with WinNonlin (version 5.1; Pharsights, Cary, NC, USA). CHO cells overexpressing SGLT1 and SGLT2 (CHO-SGLT1 and -SGLT2, respectively) and CHO-mock cells were obtained from Daewoong Pharmaceutical Co. Ltd. HEK293 cells overexpressing organic anion transporter 1 (OAT1) and OAT3 (HEK293-OAT1 and -OAT3, respectively) and HEK293-mock cells were purchased from Corning (Tewksbury, MA, USA)

Animals and Ethical Approval

Pharmacokinetic Study

Protein Binding

Results