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Chloral hydrate, through biotransformation to dichloroacetate, inhibits maleylacetoacetate isomerase and tyrosine catabolism in humans.

ABSTRACT: Chloral hydrate (CH), a sedative and metabolite of the environmental contaminant trichloroethylene, is metabolized to trichloroacetic acid, trichloroethanol, and possibly dichloroacetate (DCA). DCA is further metabolized by glutathione transferase zeta 1 (GSTZ1), which is identical to maleylacetoacetate isomerase (MAAI), the penultimate enzyme in tyrosine catabolism. DCA inhibits its own metabolism through depletion/inactivation of GSTZ1/MAAI with repeated exposure, resulting in lower plasma clearance of the drug and the accumulation of the urinary biomarker maleylacetone (MA), a metabolite of tyrosine. It is unknown if GSTZ1/MAAI may participate in the metabolism of CH or any of its metabolites and, therefore, affect tyrosine catabolism. Stable isotopes were utilized to determine the biotransformation of CH, the kinetics of its major metabolites, and the influence, if any, of GSTZ1/MAAI.Eight healthy volunteers (ages 21-40 years) received a dose of 1 g of CH (clinical dose) or 1.5 ?g/kg (environmental) for five consecutive days. Plasma and urinary samples were analyzed by gas chromatography-mass spectrometry.Plasma DCA (1.2-2.4 ?g/mL), metabolized from CH, was measured on the fifth day of the 1 g/day CH dosage but was undetectable in plasma at environmentally relevant doses. Pharmacokinetic measurements from CH metabolites did not differ between slow and fast GSTZ1 haplotypes. Urinary MA levels increased from undetectable to 0.2-0.7 ?g/g creatinine with repeated CH clinical dose exposure. Kinetic modeling of a clinical dose of 25 mg/kg DCA administered after 5 days of 1 g/day CH closely resembled DCA kinetics obtained in previously naïve individuals.These data indicate that the amount of DCA produced from clinically relevant doses of CH, although insufficient to alter DCA kinetics, is sufficient to inhibit MAAI and tyrosine catabolism, as evidenced by the accumulation of urinary MA.

SUBMITTER: Shroads AL

PROVIDER: S-EPMC4455930 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Chloral hydrate, through biotransformation to dichloroacetate, inhibits maleylacetoacetate isomerase and tyrosine catabolism in humans.

Shroads Albert L AL Coats Bonnie S BS Langaee Taimour T Shuster Jonathan J JJ Stacpoole Peter W PW

Drug metabolism and personalized therapy 20150301 1

<h4>Background</h4>Chloral hydrate (CH), a sedative and metabolite of the environmental contaminant trichloroethylene, is metabolized to trichloroacetic acid, trichloroethanol, and possibly dichloroacetate (DCA). DCA is further metabolized by glutathione transferase zeta 1 (GSTZ1), which is identical to maleylacetoacetate isomerase (MAAI), the penultimate enzyme in tyrosine catabolism. DCA inhibits its own metabolism through depletion/inactivation of GSTZ1/MAAI with repeated exposure, resulting ...[more]

PMID: 25283137

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Project description:BACKGROUNDWe aimed to test a novel method of delivery of chloral hydrate (CH) sedation in ventilated critically ill young children.METHODSChildren?<?12 years old, within 72 hours of admission, who were ventilated, receiving enteral tube-feeds, with intermittent CH ordered were enrolled after signed consent. Patients received a CH loading-dose of 10 mg/kg enterally, then a syringe-pump enteral infusion at 5 mg/kg/hour, increasing to a maximum of 9 mg/kg/hour. Cases were compared to historical controls matched for age group and Pediatric Risk of Mortality score (PRISM) category, using Fisher's exact test and the t test. The primary outcome was feasibility, defined as the use of an enteral CH continuous infusion without discontinuation attributable to a pre-specified potential harm.RESULTSThere were 21 patients enrolled, at age 11.4 (12.1) months, with bronchiolitis in 10 (48%), a mean Pediatric Logistic Organ Dysfunction (PELOD) score of 6.2 (5.2), and having received enteral CH continuous infusion for 4.5 (2.2) days. Infusion of CH was feasible in 20/21 (95%; 95% CI 76-99%) patients, with one (5%) adverse event of duodenal ulcer perforation on day 3 in a patient with croup receiving regular ibuprofen and dexamethasone. The CH infusion dose (mg/kg/h) on day 2 (n?=?20) was 8.9 (IQR 5.9, 9), and on day 4 (n?=?11) was 8.8 (IQR 7, 9). Days to titration of adequate sedation (defined as???3 PRN doses/shift) was 1 (IQR 0.5, 2.5), and hours to awakening for extubation was 5 (IQR 2, 9). Cases (versus controls) had less positive fluid balance at 48 h (-2 (45) vs. 26 (46) ml/kg, p?=?0.051), and a decrease in number of PRN sedation doses from 12 h pre to 12 hours post starting CH (4.7 (3.3) to 2.6 (2.8), p?=?0.009 versus 2.9 (3.9) to 3.4 (5), p?=?0.74). There were no statistically significant differences between cases and controls in inotrope scores, signs or treatment of withdrawal, or PICU days.CONCLUSIONSDelivering CH by continuous enteral infusion is feasible, effective, and may be associated with less positive fluid balance. Whether there is a risk of duodenal perforation requires further study.

Dataset Information

Chloral hydrate, through biotransformation to dichloroacetate, inhibits maleylacetoacetate isomerase and tyrosine catabolism in humans.

Publications

Chloral hydrate, through biotransformation to dichloroacetate, inhibits maleylacetoacetate isomerase and tyrosine catabolism in humans.

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