Elucidation of DPP-4 involvement in systemic distribution and renal reabsorption of linagliptin by PBPK modeling with a cluster Gauss-Newton method.

ABSTRACT: The dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin (LNG) exhibits target-mediated drug disposition (TMDD) in clinical settings, characterized by saturable binding to plasma soluble DPP-4 (sDPP-4) and tissue transmembrane DPP-4 (tDPP-4). Previous studies have indicated that saturable renal reabsorption of LNG contributes to its nonlinear urinary excretion observed in humans and wild-type mice, but not in Dpp-4 knockout mice. To elucidate the mechanisms underlying these complex phenomena, including DPP-4-related renal reabsorption of LNG, we employed physiologically-based pharmacokinetic (PBPK) modeling combined with a cluster Gauss-Newton method (CGNM). The CGNM facilitated the exploration of parameters in rat and human PBPK models for LNG and the determination of parameter identifiab

SUBMITTER: Nakamura R 

PROVIDER: S-EPMC11494486 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature