<i>In Vitro</i> Pharmacological Profile of Ipragliflozin, a Sodium Glucose Co-transporter 2 Inhibitor

Abstract

Ipragliflozin, a selective sodium glucose cotransporter 2 (SGLT2) inhibitor, is used for the treatment of type 2 diabetes mellitus. To date, the only known in vitro pharmacological characteristic of ipragliflozin is its selectivity for SGLT2 over SGLT1, which was previously reported by our group. Therefore, in this study, we investigated other in vitro pharmacological characteristics of ipragliflozin and compared them with those of phlorizin, a naturally occurring SGLT inhibitor. Selectivity of ipragliflozin and phlorizin for human (h) SGLT2 over hSGLT3, hSGLT4, hSGLT5, hSGLT6 and hSodium/myo-inositol (MI) cotransporter 1 (hSMIT1) was examined in Chinese hamster ovary (CHO) cells overexpressing each transporter using specific radioligands. Ipragliflozin had higher selectivity for hSGLT2 than other hSGLTs. Phlorizin showed lower selectivity for hSGLT2 compared to ipragliflozin. Studies using CHO cells overexpressing hSGLT2 demonstrated that both ipragliflozin and phlorizin competitively inhibited SGLT2-mediated methyl-α-D-glucopyranoside (AMG) uptake with an inhibitory constant (K i ) of 2.28 and 20.2 nM, respectively. Ipragliflozin, but not phlorizin, inhibited hSGLT2 in a wash-resistant manner, suggesting that binding of ipragliflozin to hSGLT2 was persistent. These data demonstrate that ipragliflozin is a competitive inhibitor of SGLT2, has high selectivity for SGLT2 over not only SGLT1 but also other SGLT family members, and binds persistently to hSGLT2.

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

“…The mode of inhibition of DWP16001 was not different from the other SGLT2 inhibitors. They all showed reversible and competitive inhibition ( Figure 10), which is consistent with other SGLT2 inhibitors [23,24]. However, the affinity to SGLT2 inhibition seemed to be different among the three SGLT2 inhibitors ( Table 3).…”

SGLT inhibitors as antidiabetic agents: a comprehensive review

“…Ipragliflozin is being used as a treatment for T2DM either alone or as an add-on to various other anti-hyperglycemic agents such as metformin (sulfonylurea), DPP-4 inhibitors or nateglinide (α-glucosidase inhibitor) and pioglitazone. 69,70 25 and 50 mg tablets of ipragliflozin have been approved, administered as a dose of 50 mg per day either before or after breakfast. The ipragliflozin dose can be increased up to 100 mg per day if 50 mg is found to be insufficient.…”

“…Very recently, in December 2018, Astellas Pharma and Kotobuki pharmaceutical Co. Ltd. got approval for Suglat for the additional indication of T1DM in Japan. 69,70 After in vitro pharmacological studies, ipragliflozin was found to inhibit SGLT2 competitively and also have high selectivity for SGLT2 over other members of the SGLT family. 69 …”

“… 69,70 After in vitro pharmacological studies, ipragliflozin was found to inhibit SGLT2 competitively and also have high selectivity for SGLT2 over other members of the SGLT family. 69 …”

Possible Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors for Reducing Effects of Blood Glucose and also Blood Pressure

“…It inhibits SGLT-2 from the tubular side in a competitive manner. Due to the structural formula and high SGLT-2 selectivity, SGLT-2i can only act at the proximal tubule at clinical pharmacological concentrations [13]. From various studies, SGLT-2i can cause not only urinary glucose excretion but also several suppressive actions on the cardiovascular event including the effect of lowering blood pressure.…”