Preclinical metabolism and disposition of luseogliflozin, a novel antihyperglycemic agent.
1. We investigated the metabolism and disposition of luseogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, in rats and dogs, as well as in vitro metabolism in rats, dogs and humans. In addition, we studied its localization in the rat kidney. 2. [14C]Luseogliflozin was rapidly and well absorbed (>86% of the dose) after oral administration to rats and dogs. The drug-derived radioactivity was mainly excreted via the feces in both species. 3. The predominant radioactivity component in the excreta was associated with the metabolites, with only a minor fraction of unchanged luseogliflozin. The major metabolites were two glucuronides (M8 and M16) in the rats, and the O-deethylated form (M2) and other oxidative metabolites (M3 and M17) in the dogs. 4. The in vitro metabolism in dog and human hepatocytes was significantly slower than that in the rat hepatocytes. The biotransformation in animal hepatocytes was similar to that observed in vivo. Incubation with human hepatocytes resulted in the formation of metabolites, including M2, M3, M8 and M17, via multiple metabolic pathways. 5. [14C]Luseogliflozin was well-distributed to its target organ, the kidney, and was found to be localized in the renal cortex, which shows SGLT2 expression. This characteristic distribution was inhibited by preinjection of phlorizin, an SGLT inhibitor, suggesting that the renal radioactivity was associated with SGLT2.
a Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd. , Saitama , Japan .
Masatoshi
M
Hasegawa
a Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd. , Saitama , Japan .
Yukihiro
Y
Chino
a Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd. , Saitama , Japan .
Nobuko
N
Horiuchi
a Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd. , Saitama , Japan .
Kenji
K
Hachiuma
a Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd. , Saitama , Japan .
Masahiro
M
Ishida
b Development Management, Taisho Pharmaceutical Co., Ltd. , Tokyo , Japan , and.
Yoshiki
Y
Fukasawa
c Development Headquarters, Taisho Pharmaceutical Co., Ltd. , Tokyo , Japan.
Yasuhiro
Y
Nakai
a Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd. , Saitama , Japan .
Jun-ichi
J
Yamaguchi
D000818:Animals; D001711:Biotransformation; D001798:Blood Proteins; D004285:Dogs; D005243:Feces / Q000737:chemistry; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D007668:Kidney / Q000378:metabolism; D010084:Oxidation-Reduction; D010695:Phlorhizin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013012:Sorbitol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014018:Tissue Distribution
D001798:Blood Proteins; D007004:Hypoglycemic Agents; C490300:Slc5a2 protein, rat; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013012:Sorbitol; C549343:1,5-anhydro-1-(5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl)-1-thioglucitol; D010695:Phlorhizin
Autoradiography; SGLT2 inhibitor; disposition; luseogliflozin; metabolism; renal distribution