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 DCAinduced 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.

Mitochondrial Glutathione Transferase Zeta 1 Is Inactivated More Rapidly by Dichloroacetate than the Cytosolic Enzyme in Adult and Juvenile Rat Liver

“…Another study of 2 month old male S-D rats indicated that hepatic cytosolic GSTZ1 activity was significantly decreased in a dose-dependent manner by DCA in the drinking water, and at the highest dose (50 mg/kg for 8 weeks), cytosolic activity had not recovered to control levels 1 week after ceasing the DCA. 39 Modeling rat pharmacokinetic data confirmed that DCA rapidly reduced its own clearance and predicted the maximum inactivation rate constant of GSTZ1 was 0.96 per h. 40 GSTZ1 activity with an endogenous substrate, MA, also was reduced after treatment with DCA. By 8 h after a single dose of DCA, cytosolic and mitochondrial activities with MA as the substrate were less than 1% of controls.…”

“…Another study of 2 month old male S-D rats indicated that hepatic cytosolic GSTZ1 activity was significantly decreased in a dose-dependent manner by DCA in the drinking water, and at the highest dose (50 mg/kg for 8 weeks), cytosolic activity had not recovered to control levels 1 week after ceasing the DCA . Modeling rat pharmacokinetic data confirmed that DCA rapidly reduced its own clearance and predicted the maximum inactivation rate constant of GSTZ1 was 0.96 per h …”

The Importance of Gender-Related Anticancer Research on Mitochondrial Regulator Sodium Dichloroacetate in Preclinical Studies In Vivo

“…Sodium dichloroacetate acts as a substrate and inhibitor of hepatic glutathione S-transferase-zeta1 (GSTζ) [101,102]. Sodium dichloroacetate inhibits its own metabolism: it can irreversibly inactivate GSTζ making itself a mechanism-based self-inhibitor [103,104]. In rats and mice, high concentrations of DCA were found to be incorporated into blood plasma proteins within 3 h of dosing [96].…”

“…The liver extraction of DCA in the GSTζ-depleted rats had linear kinetics, but it decreased with the metabolism saturation at higher doses [94]. Sodium dichloroacetate is unable to fully inhibit GSTζ activity in rats, and the existence of a portion of DCA intrinsic hepatic clearance free from DCA self-inhibition was suggested [96,104].…”

Neuroprotective Effects and Therapeutic Potential of Dichloroacetate: Targeting Metabolic Disorders in Nervous System Diseases

“… 171 Therefore, it is theoretically possible to achieve controllable blood concentrations by administering different doses of DCA according to GSTZ1 haplotypes at the time of treatment, and it is also valuable to further develop models for the nonlinear pharmacokinetics of DCA according to age and GSTZ1 genotype. 177 …”