期刊
JOURNAL OF CLINICAL PHARMACOLOGY
卷 55, 期 1, 页码 50-55出版社
WILEY
DOI: 10.1002/jcph.371
关键词
pharmacokinetics; pharmacogenetics; congenital lactic acidosis; dichloroacetate; glutathione transferase zeta 1; maleylacetoacetate isomerase; mitochondrial disease; tyrosine
资金
- Muscular Dystrophy Association [MDA/92-95]
- Orphan Products Division of the Food and Drug Administration [FD-R-001500]
- National Institutes of Health [R01 ES07355, P42 ES07375, UL1 TR000064]
Dichloroacetate (DCA) is biotransformed by glutathione transferase zeta 1 (GSTZ1), a bifunctional enzyme that, as maleylacetoacetate isomerase (MAAI), catalyzes the penultimate step in tyrosine catabolism. DCA inhibits GSTZ1/MAAI, leading to delayed plasma drug clearance and to accumulation of potentially toxic tyrosine intermediates. Haplotype variability in GSTZ1 influences short-term DCA kinetics in healthy adults, but the impact of genotype in children treated chronically with DCA is unknown. Drug kinetics was studied in 17 children and adolescents with congenital mitochondrial diseases administered 1,2-C-13-DCA. Plasma drug half-life and trough levels varied 3-6-fold, depending on GSTZ1/MAAI haplotype and correlated directly with urinary maleylacetone, a substrate for MAAI. However, chronic DCA exposure did not lead to progressive accumulation of plasma drug concentration; instead, kinetics parameters plateaued, consistent with the hypothesis that equipoise is established between the inhibitory effect of DCA on GSTZ1/MAAI and new enzyme synthesis. GSTZ1/MAAI haplotype variability affects DCA kinetics and biotransformation. However, these differences appear to be stable in most individuals and are not associated with DCA plasma accumulation or drug-associated toxicity in young children.
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