RT Journal Article
SR Electronic
T1 In Vitro–In Vivo Correlation of the Inhibition Potency of Sodium-Glucose Cotransporter Inhibitors in Rat: A Pharmacokinetic and Pharmacodynamic Modeling Approach
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 52
OP 61
DO 10.1124/jpet.113.203125
VO 345
IS 1
A1 Koji Yamaguchi
A1 Motohiro Kato
A1 Masayuki Suzuki
A1 Hitoshi Hagita
A1 Maiko Takada
A1 Miho Ayabe
A1 Yoshinori Aso
A1 Masaki Ishigai
A1 Sachiya Ikeda
YR 2013
UL http://jpet.aspetjournals.org/content/345/1/52.abstract
AB 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.