Background and Purpose-Arachidonic acid that is released following cerebral ischemia can be metabolized to . 20-HETE is a potent vasoconstrictor that may contribute to ischemic injury. This study examined the effects of blockading the synthesis of 20-HETE with TS-011 on infarct size after transient occlusion of the middle cerebral artery (MCAO) of rats and after thromboembolic stroke in monkeys. Methods-Rats were treated with TS-011 or vehicle at various times after MCAO. Infarct size was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining and plasma levels of 20-HETE were determined by liquid chromatography mass spectrometry (LC/MS). The effect of TS-011 on infarct size was also studied in monkeys after introduction of a clot into the internal carotid artery. Results-Plasma levels of 20-HETE increased after MCAO in rats. TS-011 (0.01 to 1.0 mg/kg per hour) reduced infarct volume by 40%. Chronic administration of TS-011 for 7 days reduced neurological deficits after MCAO in rats. TS-011 given in combination with tissue plasminogen activator also improved neurological outcome in the stroke model in monkeys. Conclusion-These results suggest that blockade of the formation of 20-HETE with TS-011 may be useful for the treatment of ischemic stroke.

Oct1 is possibly responsible for the plasma clearance of thiamine via tissue uptake and for milk secretion. Oct1/2 and Mate1 are involved in the renal tubular secretion of thiamine.

1. To understand the clearance mechanism of luseogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, we investigated its human metabolite profile and metabolic enzymes responsible for the primary metabolic pathways in human using reaction phenotyping. 2. Sixteen metabolites of luseogliflozin were found in human plasma and/or urine and their structural information indicated that the drug was metabolized via multiple metabolic pathways. The primary metabolic pathways involve (1) O-deethylation to form M2 and subsequent glucuronidation to form M12, (2) ω-hydroxylation at ethoxy group to form M3 followed by oxidation to form the corresponding carboxylic acid metabolite (M17) and (3) direct glucuronidation to form M8. 3. The reaction phenotyping studies indicated that the formation of M2 was mainly mediated by cytochrome P450 (CYP) 3A4/5, and subsequently M12 formation was catalyzed by UGT1A1, UGT1A8 and UGT1A9. The formation of M3 was mediated by CYP4A11, CYP4F2 and CYP4F3B, and the further oxidation of M3 to M17 was mediated by alcohol dehydrogenase and aldehyde dehydrogenase. The formation of M8 was catalyzed by UGT1A1. 4. These results demonstrate that luseogliflozin is metabolized through multiple pathways, including CYP-mediated oxidation and glucuronidation, in human.

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.

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