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.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.040048.
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ABBREVIATIONS:
- SGLT
- sodium-glucose cotransporter
- PK-PD
- pharmacokinetic and pharmacodynamic
- GFR
- glomerular filtration rate
- BBMV
- brush-border membrane vesicles
- Km,SGLT1
- Michaelis-Menten constant of SGLT1 for glucose
- Km,SGLT2
- Michaelis-Menten constant of SGLT2 for glucose
- Vmax,SGLT1
- maximal transport capacity of SGLT1 for glucose
- Vmax,SGLT2
- maximal transport capacity of SGLT2 for glucose
- Ki,SGLT1
- inhibition constant for SGLT1
- Ki,SGLT2
- inhibition constant for SGLT2
- GE
- glucose excretion rate
- GF
- glucose filtration rate
- GR
- glucose reabsorption rate
- CLR,Glc
- renal glucose clearance
- HPLC
- high-performance liquid chromatography
- T-1095
- 3-(benzo[b]furan-5-yl)-2′,6′-dihydroxy-4′-methylpropiophenone 2′-O-(6-O-methoxycarbonyl-β-d-glucopyranoside)
- AUC
- area under the curve.
- Received April 11, 2011.
- Accepted June 28, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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