Pharmacotoxicology of Trichloroethylene Metabolites

This study has been terminated.
(Difficulty in obtaining the solution from the compounding pharmacies caused a two year delay in start-up; the funding ended prior to study completion.)
Sponsor:
Information provided by (Responsible Party):
University of Florida
ClinicalTrials.gov Identifier:
NCT00865514
First received: March 17, 2009
Last updated: August 15, 2013
Last verified: July 2013
  Purpose

This project focuses on the kinetics, metabolism and human toxicology of dichloroacetate (DCA)and tyrosine catabolism. The hypothesis is that tyrosine metabolism will be greatest in subject who harbor the KRT variant for GSTz1/MAAI for which DCA exhibits a high Km.


Condition Intervention
Healthy
Drug: Dichloroacetate
Genetic: Genotyping
Other: Leucine
Other: tyrosine

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: Pharmacotoxicology of Trichloroethylene Metabolites: Short-term Effect of DCA on in Vivo Tyrosine Catabolism and MAAI Expression

Resource links provided by NLM:


Further study details as provided by University of Florida:

Primary Outcome Measures:
  • The Interaction of DCA and/or Tyrosine Breakdown Products and Maleylacetoacetate Isomerase (MAAI) in Vivo. [ Time Frame: One week ] [ Designated as safety issue: No ]

    Subjects are administered an infusion of the amino acids leucine and tyrosine. The next day they start a five day course of dichloroacetate(DCA). At the end of five days they receive another infusion of tyrosine and leucine.

    The pharmacokinetics of DCA is calculated following the second infusion.



Secondary Outcome Measures:
  • Inhibition of Tyrosine and Individual's Haplotype [ Time Frame: one week ] [ Designated as safety issue: No ]
    Given the infusion of the above amino acids and DCA administration the inhibition of tyrosine will be measured in the KRT haplotype and non KRT haplotype.


Enrollment: 2
Study Start Date: August 2011
Study Completion Date: January 2012
Primary Completion Date: January 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Haplotypes and DCA metabolism
Healthy men and women with different haplotypes will receive an infusion of leucine and tyrosine. The following day they begin a 5 day course of dichloroacetate (DCA)at a dose of 2.5mcg/kg/day. On day 6 they return and receive another infusion of leucine and tyrosine. After a 30 day washout period the subject returns and again receives an infusion of leucine and tyrosine. Then on day 2 they begin a dose of DCA at 25mg/kg for 5 days and then return for the final infusion of leucine and tyrosine.
Drug: Dichloroacetate
Healthy men and women with different haplotypes will receive an infusion of leucine and tyrosine. The following day they begin a 5 day course of dichloroacetate (DCA)at a dose of 2.5mcg/kg/day. On day 6 they return and receive another infusion of leucine and tyrosine. After a 30 day washout period the subject returns and again receives an infusion of leucine and tyrosine. Then on day 2 they begin a dose of DCA at 25mg/kg for 5 days and then return for the final infusion of leucine and tyrosine.
Other Names:
  • DCA
  • Leucine
  • Tyrosine
Genetic: Genotyping
Subjects will have 5 mls of blood drawn for genotyping
Other Names:
  • gene
  • haplotype
Other: Leucine
Healthy men and women with different haplotypes will receive an infusion of leucine and tyrosine. The following day they begin a 5 day course of dichloroacetate (DCA)at a dose of 2.5mcg/kg/day. On day 6 they return and receive another infusion of leucine and tyrosine. After a 30 day washout period the subject returns and again receives an infusion of leucine and tyrosine. Then on day 2 they begin a dose of DCA at 25mg/kg for 5 days and then return for the final infusion of leucine and tyrosine.
Other Names:
  • amino acid
  • leucine
Other: tyrosine
Healthy men and women with different haplotypes will receive an infusion of leucine and tyrosine. The following day they begin a 5 day course of dichloroacetate (DCA)at a dose of 2.5mcg/kg/day. On day 6 they return and receive another infusion of leucine and tyrosine. After a 30 day washout period the subject returns and again receives an infusion of leucine and tyrosine. Then on day 2 they begin a dose of DCA at 25mg/kg for 5 days and then return for the final infusion of leucine and tyrosine.
Other Names:
  • amino acid
  • tyrosine

Detailed Description:

Specific Aim 4. Quantify the effects of DCA on human tyrosine metabolism and on its own biotransformation in relation to dose and genotype.

  Eligibility

Ages Eligible for Study:   22 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Adults scheduled for elective surgery for benign liver disease.
  • Normal EKG and history
  • Normal baseline labs

Exclusion Criteria:

  • Pregnancy
  • severe anemia, defined as a hematocrit < 30%.
  • diabetes mellitus
  • renal insufficiency, defined as a serum creatinine > 1.5 mg/dl or a creatinine clearance < 60 ml/min
  • elevated liver enzymes
  • psychiatric illness requiring medication
  • primary biliary cirrhosis or any other form of cirrhosis
  • viral hepatitis or non-viral steatohepatitis
  • coronary heart disease, defined as requiring daily administration of anti-anginal drugs or as New York Heart Association Class III or IV heart failure
  • malignancy of any type in any anatomical location
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00865514

Locations
United States, Florida
University of Florida
Gainesville, Florida, United States, 32610
Sponsors and Collaborators
University of Florida
Investigators
Principal Investigator: Peter W Stacpoole, PhD, MD University of Florida
  More Information

Publications:
Page N. Assessment of trichloroethylene as an occupational carcinogen. In: Davis W, Rosenfeld C, eds. Carcinogenic risks: strategies for intervention INSERM Symposia series Vol. 74. Lyon, France: International Agency for Reserach on Cancerl; IARC Scientific Publications E No. 25, 1979.
Westrick JJ, Mello JW, Thomas RF. The groundwater supply survey. J Am Water Works 76:52, 1984.
Josephson J. Implementing superfund. Environ Sci Technol 20:23, 1986.
Miller JW, Uden PC. Characterization of nonvolatile aqueous chlorination products of humic substances. Environ Sci Technol 17:150-157, 1983.
Uden PCC, Miller JW. Chlorinated acids and chloral in drinking water. J Amer Water Works Assoc 75:524-527, 1983.
Jolley RL. Basic issues in water chlorination: a chemical perspective. In, Water chlorination: chemistry, environmental impact and health effects. Lewis Publ, Inc. Chelsea, MI 5:19-38, 1985.
Salmon AG, Jackson RJ, Smith MT. Chloral hydrate: cancer risk assessment of a drug previously presumed safe. The Toxicologist 11:350, 1991.
Toxicological review of dichloroacetic acid (CAS No. 79-43-6). U.S. Environ. Protection Agency. Washington, DC, August, 2003.
Gonzalez-Leon A, Schultz IR, Bull RJ. Species differences in the toxicokinetics of dichloroacetate and trichloroacetate in F344 rats and B6C3F1 mice after prolonged administration in drinking water. Fundam Appl Toxicol Suppl 36, Abst. 168, p. 33, 1997.
NTP Technical Report. Toxicology and carcinogenesis study of chloral hydrate. NIH Publication No. 03-4437, 2002.
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Chloral hydrate. World Health Organization, 2004, pp. 317-358.
Kinter M, Sherman NE. Peptide Sequencng andIdentifcation Using Tandem Mass Specrometry. John Wiley and Sons, Inc., pp. 147-165, 2000.

Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT00865514     History of Changes
Other Study ID Numbers: 14617-CP-001, 5R01ES014617
Study First Received: March 17, 2009
Results First Received: March 21, 2013
Last Updated: August 15, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Florida:
dichloroacetate
tyrosine
maleylacetoacetate
trichloroethylene
leucine
haplotype

Additional relevant MeSH terms:
Trichloroethylene
Anesthetics, Inhalation
Anesthetics, General
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 16, 2014