title: Pharmacokinetic and pharmacodynamic modeling of the effect of an sodium-glucose cotransporter inhibitor, phlorizin, on renal glucose transport in rats.
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.
authors.affiliation: Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. yamaguchikuj@chugai-pharm.co.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Motohiro
authors.initials: M
authors.lastname: Kato
authors.forename: Masayuki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Kimie
authors.initials: K
authors.lastname: Asanuma
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Aso
authors.forename: Sachiya
authors.initials: S
authors.lastname: Ikeda
authors.forename: Masaki
authors.initials: M
authors.lastname: Ishigai
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010695:Phlorhizin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D022161:Transport Vesicles / Q000187:drug effects / Q000378:metabolism
chemical_list: D001786:Blood Glucose; C495676:Slc5a1 protein, rat; C490300:Slc5a2 protein, rat; D051269:Sodium-Glucose Transporter 1; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D012964:Sodium; D010695:Phlorhizin; D005947:Glucose