A Mechanism-Based Pharmacokinetic Enzyme Turnover Model for Dichloroacetic Acid Autoinhibition in Rats.

ABSTRACT: Dichloroacetic acid (DCA), a halogenated organic acid, is a pyruvate dehydrogenase kinase inhibitor that has been used to treat congenital or acquired lactic acidosis and is currently in early-phase clinical trials for cancer treatment. DCA was found to inhibit its own metabolism by irreversibly inactivating glutathione transferase zeta 1 (GSTZ1-1), resulting in nonlinear kinetics and abnormally high accumulation ratio after repeated dosing. In this analysis, a semi-mechanistic pharmacokinetic enzyme turnover model was developed for the first time to capture DCA autoinhibition, gastrointestinal region-dependent absorption, and time-dependent change in bioavailability in rats. The maximum rate constant for DCA-induced GSTZ1-1 inactivation is estimated to be 0.96/h, which is 110 times that o

SUBMITTER: Jiang Y 

PROVIDER: S-EPMC5553688 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature