title: In vitro-in vivo correlation of the inhibition potency of sodium-glucose cotransporter inhibitors in rat: a pharmacokinetic and pharmacodynamic modeling approach.
abstract: To evaluate the relationship between the in vitro and in vivo potency of sodium-glucose cotransporter (SGLT) inhibitors, a pharmacokinetic and pharmacodynamic (PK-PD) study was performed using normal rats. A highly selective SGLT2 inhibitor, tofogliflozin, and four other inhibitors with different in vitro inhibition potency to SGLT2 and selectivity toward SGLT2, versus SGLT1 were used as test compounds, and the time courses for urinary glucose excretion (UGE) and the plasma glucose and compound concentrations were monitored after administration of the compounds. A PK-PD analysis of the UGE caused by SGLT inhibition was performed on the basis of a nonlinear parallel tube model that took into consideration the consecutive reabsorption by different glucose transport properties of SGLT2 and SGLT1. The model adequately captured the time course of cumulative UGE caused by SGLT inhibition; then, the in vivo inhibition constants (Ki) of inhibitors for both SGLT1 and SGLT2 were estimated. The in vivo selectivity toward SGLT2 showed a good correlation with the in vitro data (r = 0.985; P < 0.05), with in vivo Ki values for SGLT2 in the range of 0.3-3.4-fold the in vitro data. This suggests that in vitro inhibition potency to both SGLT2 and SGLT1 is reflected in vivo. Furthermore, the complementary role of SGLT1 to SGLT2 and how selectivity toward SGLT2 affects the inhibitory potency for renal glucose reabsorption were discussed using the PK-PD model.
authors: Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. yamaguchikuj@chugai-pharm.co.jp
authors: Koji
authors: K
authors: Yamaguchi
authors: Motohiro
authors: M
authors: Kato
authors: Masayuki
authors: M
authors: Suzuki
authors: Hitoshi
authors: H
authors: Hagita
authors: Maiko
authors: M
authors: Takada
authors: Miho
authors: M
authors: Ayabe
authors: Yoshinori
authors: Y
authors: Aso
authors: Masaki
authors: M
authors: Ishigai
authors: Sachiya
authors: S
authors: Ikeda
mesh_terms: D000818:Animals; D001692:Biological Transport; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D015394:Molecular Structure; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors*; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D053719:Tandem Mass Spectrometry
chemical_list: D007004:Hypoglycemic Agents; C495676:Slc5a1 protein, rat; C490300:Slc5a2 protein, rat; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D005947:Glucose