title: Characterization and comparison of sodium-glucose cotransporter 2 inhibitors in pharmacokinetics, pharmacodynamics, and pharmacologic effects.
abstract: The sodium-glucose cotransporter (SGLT) 2 offer a novel approach to treating type 2 diabetes by reducing hyperglycaemia via increased urinary glucose excretion. In the present study, the pharmacokinetic, pharmacodynamic, and pharmacologic properties of all six SGLT2 inhibitors commercially available in Japan were investigated and compared. Based on findings in normal and diabetic mice, the six drugs were classified into two categories, long-acting: ipragliflozin and dapagliflozin, and intermediate-acting: tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin. Long-acting SGLT2 inhibitors exerted an antihyperglycemic effect with lower variability of blood glucose level via a long-lasting increase in urinary glucose excretion. In addition, ipragliflozin and luseogliflozin exhibited superiority over the others with respect to fast onset of pharmacological effect. Duration and onset of the pharmacologic effects seemed to be closely correlated with the pharmacokinetic properties of each SGLT2 inhibitor, particularly with respect to high distribution and long retention in the target organ, the kidney. While all six SGLT2 inhibitors were significantly effective in increasing urinary glucose excretion and reducing hyperglycemia, our findings suggest that variation in the quality of daily blood glucose control associated with duration and onset of pharmacologic effects of each SGLT2 inhibitor might cause slight differences in rates of improvement in type 2 diabetes.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan. Electronic address: atsuo.tahara@jp.astellas.com.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Tahara
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takasu
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Yokono
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Imamura
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kurosaki
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D001786:Blood Glucose; D000068896:Canagliflozin / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D003692:Delayed-Action Preparations; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D005960:Glucosides / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D006029:Glycosuria; D007004:Hypoglycemic Agents; D008297:Male; D008813:Mice, Inbred ICR; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013012:Sorbitol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D013876:Thiophenes / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: D001559:Benzhydryl Compounds; D001786:Blood Glucose; D003692:Delayed-Action Preparations; D005960:Glucosides; D007004:Hypoglycemic Agents; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013876:Thiophenes; D000068896:Canagliflozin; C529054:dapagliflozin; C572941:ipragliflozin; D013012:Sorbitol; C549343:1,5-anhydro-1-(5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl)-1-thioglucitol; C570240:empagliflozin; C575086:6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol
keywords: Diabetes; Hyperglycemia; Hyperinsulinemia; SGLT2 inhibitor; Urinary glucose excretion