Pharmacokinetic and Pharmacodynamic Modeling of the Effect of an Sodium-Glucose Cotransporter Inhibitor, Phlorizin, on Renal Glucose Transport in Rats

Abstract

ABSTRACT:A pharmacokinetic and pharmacodynamic (PK-PD) model for the inhibitory effect of sodium-glucose cotransporter (SGLT) inhibitors on renal glucose reabsorption was developed to predict in vivo efficacy. First, using the relationship between renal glucose clearance and plasma glucose level in rats and both the glucose affinity and transport capacity obtained from in vitro vesicle experiments, a pharmacodynamic model analysis was performed based on a nonlinear parallel tube model to express the renal glucose transport mediated by SGLT1 and SGLT2. This model suitably expressed the relationship between plasma glucose level and renal glucose excretion. A PK-PD model was developed next to analyze the inhibitory effect of phlorizin on renal glucose reabsorption. The PK-PD model analysis was performed using averaged concentrations of both the drug and glucose in plasma and the corresponding renal glucose clearance. The model suitably expressed the concentration-dependent inhibitory effect of phlorizin on renal glucose reabsorption. The in vivo inhibition constants of phlorizin for SGLT in rats were estimated to be 67 nM for SGLT1 and 252 nM for SGLT2, which are similar to the in vitro data reported previously. This suggests that the in vivo efficacy of SGLT inhibitors could be predicted from an in vitro study based on the present PK-PD model. The present model is based on physiological and biochemical parameters and, therefore, would be helpful in understanding individual differences in the efficacy of an SGLT inhibitor.

Effect of dapagliflozin on colon cancer cell [Rapid Communication]

“…As shown in Fig. 2, there was no significant effect of phlorizn on HCT116 cell attachment at doses known to inhibit SGTL2 [7].…”

In Vitro–In Vivo Correlation of the Inhibition Potency of Sodium-Glucose Cotransporter Inhibitors in Rat: A Pharmacokinetic and Pharmacodynamic Modeling Approach

“…The glucose concentrations in plasma and urine samples were determined using a Glucose CII-Test Wako kit (Wako Pure Chemical Industries, Ltd., Osaka, Japan). The PK-PD data of phlorizin was cited from a previous report (Yamaguchi et al, 2011).…”

“…f u was calculated as the mean value of three experiments. The f u values of tofogliflozin (Suzuki et al, 2012) and phlorizin (Yamaguchi et al, 2011) were cited from previous reports. PK-PD Studies of SGLT Inhibitors in Rats.…”

“…We used tofogliflozin and other inhibitors with different in vitro inhibition potency to SGLT2 and selectivity toward SGLT2 as the test compounds and performed pharmacokinetic and pharmacodynamic (PK-PD) studies of them with use of normal rats. We previously developed a mechanism-based PK-PD model in which the different glucose transport properties between SGLT1 and SGLT2 were considered (Yamaguchi et al, 2011). The model was able to describe the plasma glucose-dependent UGE in rats; moreover, it could estimate the in vivo inhibition constants of SGLT1 and SGLT2 for phlorizin, which has less selectivity toward SGLT2.…”

Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling of Luseogliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, in Japanese Patients with Type 2 Diabetes Mellitus

“…Although previous studies have reported particular PK-PD models to evaluate the UGE of SGLT2 inhibitors, [13][14][15][16][17][18][19] only four have adopted the mechanism-based PK-PD models: the PK-PD model for tofogliflozin in rats 16,17) and the PK-PD model of dapagliflozin and canagliflozin in humans. 18,19) In these studies, the investigators adopted the physiological construction of the proximal tubule in the kidney and the kinetics of competitive SGLT1/2 inhibition in their PK-PD model and successfully described the time course of UGE.…”