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J Pharm Sci. 2017 May;106(5):1396-1404. doi: 10.1016/j.xphs.2017.01.032. Epub 2017 Feb 3.

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

Author information

1
Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa 52242.
2
Division of Applied Clinical Sciences, Department of Pharmacy Practice and Science, College of Pharmacy, University of Iowa, Iowa 52242.
3
Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Florida 32611.
4
Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa 52242. Electronic address: guohua-an@uiowa.edu.

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 of the rate constant for GSTZ1-1 natural degradation (0.00875/h). The model-predicted DCA concentration that corresponds to 50% of maximum enzyme inhibition (EC50) is 4.32 mg/L. The constructed pharmacokinetic enzyme turnover model, when applied to human data, could be used to predict the accumulation of DCA after repeated oral dosing, guide selection of dosing regimens in clinical studies, and facilitate clinical development of DCA.

KEYWORDS:

bioavailability; inhibition; pharmacokinetics; physiological model

PMID:
28163135
PMCID:
PMC5553688
DOI:
10.1016/j.xphs.2017.01.032
[Indexed for MEDLINE]
Free PMC Article

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