Mechanistic evaluation of the inhibitory effect of four SGLT-2 inhibitors on SGLT 1 and SGLT 2 using physiologically based pharmacokinetic (PBPK) modeling approaches
- PMID: 37342592
- PMCID: PMC10277867
- DOI: 10.3389/fphar.2023.1142003
Mechanistic evaluation of the inhibitory effect of four SGLT-2 inhibitors on SGLT 1 and SGLT 2 using physiologically based pharmacokinetic (PBPK) modeling approaches
Abstract
Sodium-glucose co-transporter type 2 (SGLT 2, gliflozins) inhibitors are potent orally active drugs approved for managing type 2 diabetes. SGLT 2 inhibitors exert a glucose-lowering effect by suppressing sodium-glucose co-transporters 1 and 2 in the intestinal and kidney proximal tubules. In this study, we developed a physiologically based pharmacokinetic (PBPK) model and simulated the concentrations of ertugliflozin, empagliflozin, henagliflozin, and sotagliflozin in target tissues. We used the perfusion-limited model to illustrate the disposition of SGLT 2 inhibitors in vivo. The modeling parameters were obtained from the references. Simulated steady-state plasma concentration-time curves of the ertugliflozin, empagliflozin, henagliflozin, and sotagliflozin are similar to the clinically observed curves. The 90% prediction interval of simulated excretion of drugs in urine captured the observed data well. Furthermore, all corresponding model-predicted pharmacokinetic parameters fell within a 2-fold prediction error. At the approved doses, we estimated the effective concentrations in intestinal and kidney proximal tubules and calculated the inhibition ratio of SGLT transporters to differentiate the relative inhibition capacities of SGLT1 and 2 in each gliflozin. According to simulation results, four SGLT 2 inhibitors can nearly completely inhibit SGLT 2 transporter at the approved dosages. Sotagliflozin exhibited the highest inhibition activity on SGLT1, followed by ertugliflozin, empagliflozin, and henagliflozin, which showed a lower SGLT 1 inhibitory effect. The PBPK model successfully simulates the specific target tissue concentration that cannot be measured directly and quantifies the relative contribution toward SGLT 1 and 2 for each gliflozin.
Keywords: SGLT2 inhibitors; inhibitory effect; physiologically-based pharmacokinetic model; sodium-glucose cotransporter 1 and 2; type 2 diabetes mellitus (T2DM).
Copyright © 2023 Zhang, Xie, Li, Chen and Shi.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
-
- Buse J. B., Wexler D. J., Tsapas A., Rossing P., Mingrone G., Mathieu C., et al. (2020). 2019 update to: Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American diabetes association (ADA) and the European association for the study of diabetes (easd). Diabetes Care 43 (2), 487–493. 10.2337/dci19-0066 - DOI - PMC - PubMed
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