Pharmacological profile of ipragliflozin (ASP1941), a novel selective SGLT2 inhibitor, in vitro and in vivo

Abstract

The pharmacological profile of ipragliflozin (ASP1941; (1S)-1,5-anhydro-1-C-{3-[(1-benzothiophen-2-yl)methyl]-4-fluorophenyl}-D: -glucitol compound with L: -proline (1:1)), a novel SGLT2 selective inhibitor, was investigated. In vitro, the potency of ipragliflozin to inhibit SGLT2 and SGLT1 and stability were assessed. In vivo, the pharmacokinetic and pharmacologic profiles of ipragliflozin were investigated in normal mice, streptozotocin-induced type 1 diabetic rats, and KK-A(y) type 2 diabetic mice. Ipragliflozin potently and selectively inhibited human, rat, and mouse SGLT2 at nanomolar ranges and exhibited stability against intestinal glucosidases. Ipragliflozin showed good pharmacokinetic properties following oral dosing, and dose-dependently increased urinary glucose excretion, which lasted for over 12 h in normal mice. Single administration of ipragliflozin resulted in dose-dependent and sustained antihyperglycemic effects in both diabetic models. In addition, once-daily ipragliflozin treatment over 4 weeks improved hyperglycemia with a concomitant increase in urinary glucose excretion in both diabetic models. In contrast, ipragliflozin at pharmacological doses did not affect normoglycemia, as was the case with glibenclamide, and did not influence intestinal glucose absorption and electrolyte balance. These results suggest that ipragliflozin is an orally active SGLT2 selective inhibitor that induces sustained increases in urinary glucose excretion by inhibiting renal glucose reabsorption, with subsequent antihyperglycemic effect and a low risk of hypoglycemia. Ipragliflozin has, therefore, the therapeutic potential to treat hyperglycemia in diabetes by increasing glucose excretion into urine.

Efficacy and safety of sodium–glucose cotransporter 2 inhibitor ipragliflozin on glycemic control and cardiovascular parameters in Japanese patients with type 2 diabetes mellitus; Fukuoka Study of Ipragliflozin (FUSION)

“…Ipragliflozin (Ipra) is an SGLT2I that is made in Japan [5] and was the first SGLT2I to enter clinical use in Japan. In clinical trials conducted before it was made available, the efficacy and safety of Ipra for its glucoselowering effect was established in a phase 3, randomized, placebo-controlled trial [6].…”

A Strategy for Assessing Potential Drug-Drug Interactions of a Concomitant Agent against a Drug Absorbed via an Intestinal Transporter in Humans

“…info.pmda.go.jp/downfiles/ph/PDF/800126_3969018F1022_1_01.pdf). Based on this information, we evaluated the DDI potential between ipragliflozin and miglitol retrospectively according to our proposed approach using the published IC 50 value (1876 nM) for hSGLT1 (Tahara et al, 2012) and human PK data for ipragliflozin (Zhang et al, 2013). The resulting TAIC/T max was estimated to be 116%, predicting that ipragliflozin may interact with miglitol absorption in humans.…”

Chances and risks of SGLT2 inhibitors

“…Therefore, inadequate fluid intake, in particular by elderly patients, could cause problems of dehydration. Notably, increase in serum sodium (hypernatremia) as a sequel of dehydration was not observed, at least in animal models as reported by Tahara et al (2011). This could be due to the fact that SGLT2 is a co-transporter for sodium and glucose so that sodium is also excreted, along with water, upon blockade of this carrier.…”

“…Many pharmacologists and clinicians may ask whether this concept may not be too simple. The work of Tahara et al (2011) presents original data on the pharmacodynamic effects of a new representative of the SGLT2 inhibitor class, ipragliflozin, which highlights the perspectives and potentials but also potential drawbacks of SGLT2 inhibition. These pharmacodynamic data, along with theoretical considerations based on known physiological mechanisms, can help in identifying potential risks of this approach.…”