Pharmacogenetic Considerations with Dichloroacetate Dosing

James, Margaret O.; Stacpoole, Peter W.

doi:10.2217/pgs-2015-0012

Cited by 29 publications

(25 citation statements)

References 61 publications

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“…However, we did not observe DCA effects on AbGC survival or other phenotypic modifications such as changes in cell morphology, expression, or distribution of AbGC cell markers. DCA actions on cell growth depend on variable molecular mechanisms associated with metabolic state, aging, and/or alterations in mitochondrial ETC [37][38][39]. In our model, mitochondrial ETC operation seems not to be compromised, as AbGC were capable to enhance cell RCR in response to DCA treatment.…”

Section: Discussionmentioning

confidence: 74%

“…DCA is metabolized to glyoxylate (which is inactive toward PDHC) by glutathione transferase zeta1 (GSTZ1). Genetic variation in GSTZ1 haplotype has been established as 1 of the principal variables influencing DCA kinetics and dynamics in humans apart from previous exposure to DCA [38]. Indeed, personalized dosing of DCA by GSTZ1 genotyping has been recently reported [51].…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial Modulation by Dichloroacetate Reduces Toxicity of Aberrant Glial Cells and Gliosis in the SOD1G93A Rat Model of Amyotrophic Lateral Sclerosis

et al. 2019

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron (MN) degeneration and gliosis. Neonatal astrocytes obtained from the SOD1G93A rat model of ALS exhibit mitochondrial dysfunction and neurotoxicity that can be reduced by dichloroacetate (DCA), a metabolic modulator that has been used in humans, and shows beneficial effects on disease outcome in SOD1G93A mice. Aberrant glial cells (AbGC) isolated from the spinal cords of adult paralytic SOD1G93A rats exhibit highly proliferative and neurotoxic properties and may contribute to disease progression. Here we analyze the mitochondrial activity of AbGC and whether metabolic modulation would modify their phenotypic profile. Our studies revealed fragmented mitochondria and lower respiratory control ratio in AbGC compared to neonatal SOD1G93A and nontransgenic rat astrocytes. DCA (5 mM) exposure improved AbGC mitochondrial function, reduced their proliferative rate, and importantly, decreased their toxicity to MNs. Furthermore, oral DCA administration (100 mg/kg, 10 days) to symptomatic SOD1G93A rats reduced MN degeneration, gliosis, and the number of GFAP/S100β double-labeled hypertrophic glial cells in the spinal cord. DCA treatment of AbGC reduced extracellular lactate levels indicating that the main recognized DCA action, targeting the pyruvate dehydrogenase kinase/pyruvate dehydrogenase complex, may underlie our findings. Our results show that AbGC metabolic phenotype is related to their toxicity to MNs and indicate that its modulation can reduce glial mediated pathology in the spinal cord. Together with previous findings, these results further support glial metabolic modulation as a valid therapeutic strategy in ALS.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Mitochondrial Modulation by Dichloroacetate Reduces Toxicity of Aberrant Glial Cells and Gliosis in the SOD1G93A Rat Model of Amyotrophic Lateral Sclerosis

et al. 2019

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“…Of these, three non-synonymous SNPs in the coding region (rs7975, rs7972, rs1046428) have been identified in people and give rise to five commonly found haplotypes of GSTZ1 , shown in Table 2 (Blackburn, et al, 2001; Shroads, et al, 2012). As recently reviewed (James & Stacpoole, 2016), the incidence of these haplotypes varied somewhat with ethnic group, however in all groups studied to date, GSTZ1C , coding for glutamic acid at position 32, glycine at position 42 and threonine at position 82 of the expressed enzyme protein is the most common. GSTZ1C is also referred to as EGT, highlighting the variant amino acids.…”

Section: Polymorphisms Of Gstz1 In Humansmentioning

confidence: 98%

“…Similar results were found with children (Shroads, et al, 2015). As recently reviewed (James & Stacpoole, 2016) individuals can be considered to fall into rapid (at least one copy of the GSTZ1C gene) and slow metabolizer (no copy of GSTZ1C ) phenotypes with respect to DCA following administration of multiple doses.…”

Section: Polymorphisms Of Gstz1 In Humansmentioning

confidence: 99%

Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

James

Jahn

Zhong

et al. 2017

Pharmacology & Therapeutics

106

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Dichloroacetate (DCA) has several therapeutic applications based on its pharmacological property of inhibiting pyruvate dehydrogenase kinase. DCA has been used to treat inherited mitochondrial disorders that result in lactic acidosis, as well as pulmonary hypertension and several different solid tumors, the latter through its ability to reverse the Warburg effect in cancer cells and restore aerobic glycolysis. The main clinically limiting toxicity is reversible peripheral neuropathy. Although administration of high doses to rodents can result in liver cancer, there is no evidence that DCA is a human carcinogen. In all studied species, including humans, DCA has the interesting property of inhibiting its own metabolism upon repeat dosing, resulting in alteration of its pharmacokinetics. The first step in DCA metabolism is conversion to glyoxylate catalyzed by glutathione transferase zeta 1 (GSTZ1), for which DCA is a mechanism-based inactivator. The rate of GSTZ1 inactivation by DCA is influenced by age, GSTZ1 haplotype and cellular concentrations of chloride. The effect of DCA on its own metabolism complicates the selection of an effective dose with minimal side effects.

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“…Moreover, plasma half‐life increased approximately 10‐fold after 6 months of daily administration in adults, whereas half‐life increased only about 2.5‐fold in children, suggesting that age‐dependent changes may play a role in the metabolism of DCA . Finally, it is known that GSTZ1 is polymorphic, resulting in the expression of 5 major haplotypes: EGT (wild type, 45%–55% of the population), KGT (25%–35% of the population), EGM (10%–20% of the population), KRT (1%–10% of the population), and KGM (<1% of the population) . Subjects who have at least 1 EGT allele (EGT carriers) clear the drug from plasma faster than those who do not possess EGT allele(s) (EGT noncarriers).…”

mentioning

confidence: 99%

Model Informed Dose Optimization of Dichloroacetate for the Treatment of Congenital Lactic Acidosis in Children

Mangal

James

Stacpoole

et al. 2017

The Journal of Clinical Pharma

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Dichloroacetate (DCA) is an investigational drug used to treat congenital lactic acidosis and other mitochondrial disorders. Response to DCA therapy in young children may be suboptimal following body weight–based dosing. This is because of autoinhibition of its metabolism, age-dependent changes in pharmacokinetics, and polymorphisms in glutathione transferase zeta 1 (GSTZ1), its primary metabolizing enzyme. Our objective was to predict optimal DCA doses for the treatment of congenital lactic acidosis in children. Accordingly, a semimechanistic pharmacokinetic-enzyme turnover model was developed in a step-wise approach: (1) a population pharmacokinetic model for adults was developed; (2) the adult model was scaled to children using allometry and physiology-based scaling; and (3) the scaled model was externally qualified, updated with clinical data, and optimal doses were projected. A 2-compartment model accounting for saturable clearance and GSTZ1 enzyme turnover successfully characterized the DCA PK in adults and children. DCA-induced inactivation of GSTZ1 resulted in phenoconversion of all subjects into slow metabolizers after repeated dosing. However, rate and extent of inactivation was 2-fold higher in subjects without the wild-type EGT allelic variant of GSTZ1, resulting in further phenoconversion into ultraslow metabolizers after repeated DCA administration. Furthermore, DCA-induced GSTZ1 inactivation rate and extent was found to be 25-to 30-fold lower in children than in adults, potentially accounting for the observed age-dependent changes in PK. Finally, a 12.5 and 10.6 mg/kg twice-daily DCA dose was optimal in achieving the target steady-state trough concentrations (5–25 mg/L) for EGT carrier and EGT noncarrier children, respectively.

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Pharmacogenetic Considerations with Dichloroacetate Dosing

Cited by 29 publications

References 61 publications

Mitochondrial Modulation by Dichloroacetate Reduces Toxicity of Aberrant Glial Cells and Gliosis in the SOD1G93A Rat Model of Amyotrophic Lateral Sclerosis

Mitochondrial Modulation by Dichloroacetate Reduces Toxicity of Aberrant Glial Cells and Gliosis in the SOD1G93A Rat Model of Amyotrophic Lateral Sclerosis

Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1

Model Informed Dose Optimization of Dichloroacetate for the Treatment of Congenital Lactic Acidosis in Children

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