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Sodium-glucose cotransporter 1 (SGLT1) is the primary transporter for glucose absorption from digested nutrients in the gastrointestinal tract. Intestinal SGLT1 inhibition reduces post-prandial hyperglycemia and enhances the increase of plasma glucagon-like peptide-1 (GLP-1) levels. SGL5213 is a novel and potent intestinal SGLT1 inhibitor. This study characterizes the pharmacological profiles of SGL5213 in rodents. Orally administered SGL5213 was hardly absorbed and its distribution was restricted to the gastrointestinal lumen. SGL5213 significantly improved post-prandial hyperglycemia in streptozotocin (STZ)-induced diabetic rats at doses of 1 mg/kg or more. After the oral administration of starch, SGL5213 increased the amount of residual glucose in the small intestine at 1-3 h and in the cecum and colon at 3-9 h by inhibiting glucose absorption and allowing the unabsorbed glucose to be delivered into the lower-gastrointestinal tract. In the vehicle group, the plasma total GLP-1 (tGLP-1) and tGLP-2 levels increased at 15 min and the plasma total glucose-dependent insulinotropic polypeptide (tGIP) level increased at 1 h after meal loading. SGL5213 at doses of 0.1 mg/kg or more enabled the plasma levels of tGLP-1 and tGLP-2 to be retained for a period of 1-6 h, compared with the vehicle group. In contrast, SGL5213 at doses of 0.3 mg/kg or more suppressed the plasma tGIP elevation after meal loading. This study demonstrated for the first time that an intestinal SGLT1 inhibitor enhanced post-prandial plasma GLP-2 secretion. These results suggest that SGL5213 might exhibit a useful pharmacological efficacy through the physiological actions of GLP-1 and GLP-2., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A strategy for assessing potential drug-drug interactions (DDIs) based on a simulated intestinal concentration is described. The proposed prediction method was applied to the DDI assessment of luseogliflozin, a novel antidiabetic drug, against miglitol absorbed via the intestinal sodium-glucose cotransporter 1 (SGLT1). The method involves four steps: collection of physicochemical and pharmacokinetic parameters of luseogliflozin for use in a computer simulation; evaluation of the validity of these parameters by verifying the goodness of fit between simulated and observed plasma profiles; simulation of the intestinal luseogliflozin concentration-time profile using the Advanced Compartment Absorption and Transit (ACAT) model in a computer program and estimation of the time spent above a value 10-fold higher than the IC50 value (TAIC) for SGLT1; and evaluation of the DDI potential of luseogliflozin by considering the percentage of TAIC against the miglitol Tmax (time for Cmax) value (TAIC/Tmax). An initial attempt to prove the validity of this method was performed in rats. The resulting TAIC/Tmax in rats was 32%, suggesting a low DDI potential of luseogliflozin against miglitol absorption. The validity was then confirmed using an in vivo interaction study in rats. In humans, luseogliflozin was expected to have no DDI potential against miglitol absorption, since the TAIC/Tmax in humans was lower than that in rats. This prediction was proven, as expected, in a clinical interaction study. In conclusion, the present strategy based on a simulation of the intestinal concentration-time profile using dynamic modeling would be useful for assessing the clinical DDI potential of a concomitant agent against drugs absorbed via an intestinal transporter., (Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.)