Using a Mathematical Modeling To Simulate Pharmacokinetics and Urinary Glucose Excretion of Luseogliflozin and Explore the Role of SGLT1/2 in Renal Glucose Reabsorption.

Abstract

(1) Purpose: To develop a mathematical model combining physiologically based pharmacokinetic and urinary glucose excretion (PBPK-UGE) to simultaneously predict pharmacokinetic (PK) and UGE changes of luseogliflozin (LUS) as well as to explore the role of sodium-glucose cotransporters (SGLT1 and SGLT2) in renal glucose reabsorption (RGR) in humans. (2) Methods: The PBPK-UGE model was built using physicochemical and biochemical properties, binding kinetics data, affinity to SGLTs for glucose, and physiological parameters of renal tubules. (3) Results: The simulations using this model clarified that SGLT1/2 contributed 15 and 85%, respectively, to RGR in the absence of LUS. However, in the presence of LUS, the contribution proportion of SGLT1 rose to 52-76% in healthy individuals and 55-83% in T2DM patients, and that of SGLT2 reduced to 24-48 and 17-45%, respectively. Furthermore, this model supported the underlying mechanism that only 23-40% inhibition of the total RGR with 5 mg of LUS is resulted from SGLT1's compensatory effect and the reabsorption activity of unbound SGLT2. (4) Conclusion: This PBPK-UGE model can predict PK and UGE in healthy individuals and T2DM patients and can also analyze the contribution of SGLT1/2 to RGR with and without LUS.