Pharmacotoxicology of Trichloroethylene Metabolites

Not Applicable

Terminated

Conditions: Healthy

Interventions: Drug: Dichloroacetate
Genetic: Genotyping
Other: Leucine
Other: tyrosine

Registration Number: NCT00865514

Lead Sponsor: University of Florida

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 2

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Haplotypes and DCA metabolism	Genotyping	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.
Haplotypes and DCA metabolism	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.
Haplotypes and DCA metabolism	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.
Haplotypes and DCA metabolism	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.

Primary Outcome Measures

Name	Time	Method
The Interaction of DCA and/or Tyrosine Breakdown Products and Maleylacetoacetate Isomerase (MAAI) in Vivo.	One week	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

Name	Time	Method
Inhibition of Tyrosine and Individual's Haplotype	one week	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.