Pharmacogenetic considerations with dichloroacetate dosing

The investigational drug dichloroacetate (DCA) is a metabolic regulator that has been successfully used to treat acquired and congenital metabolic diseases and, recently, solid tumors. Its clinical use has revealed challenges in selecting appropriate doses. Chronic administration of DCA leads to inh...

Full description

Saved in:
Bibliographic Details
Published in:Pharmacogenomics 2016-05, Vol.17 (7), p.743-753
Main Authors: James, Margaret O, Stacpoole, Peter W
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Binding sites
Biotransformation
Carbon dioxide
Chlorides - pharmacology
Diabetes
dichloroacetate
Dichloroacetic acid
Dichloroacetic Acid - administration & dosage
Dichloroacetic Acid - pharmacokinetics
Dosage
Drug dosages
Enzymes
Genomics
Glutathione transferase
Glutathione Transferase - antagonists & inhibitors
Glutathione Transferase - genetics
Glutathione Transferase - metabolism
GSTZ1
Haplotypes
Humans
In Vitro Techniques
Kinases
Liver
Liver - metabolism
Metabolic Diseases - drug therapy
Metabolic Diseases - genetics
Metabolic Diseases - metabolism
Metabolic disorders
Metabolism
Metabolites
Neoplasms - drug therapy
Neoplasms - genetics
Neoplasms - metabolism
pharmacogenetics
Pharmacogenomic Testing
Pharmacogenomic Variants
Pharmacokinetics
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
Protein-Serine-Threonine Kinases - adverse effects
Review
Single-nucleotide polymorphism
Solid tumors
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:The investigational drug dichloroacetate (DCA) is a metabolic regulator that has been successfully used to treat acquired and congenital metabolic diseases and, recently, solid tumors. Its clinical use has revealed challenges in selecting appropriate doses. Chronic administration of DCA leads to inhibition of DCA metabolism and potential accumulation to levels that result in side effects. This is because conversion of DCA to glyoxylate is catalyzed by one enzyme, glutathione transferase zeta 1 (GSTZ1-1), which is inactivated by DCA. SNPs in the gene result in expression of polymorphic variants of the enzyme that differ in activity and rates of inactivation by DCA under physiological conditions: these properties lead to considerable variation between people in the pharmacokinetics of DCA.
ISSN:1462-2416
1744-8042
DOI:10.2217/pgs-2015-0012