Pharmacotoxicology of Trichloroethylene Metabolites

Not Applicable

Completed

Conditions: Congenital Lactic Acidosis

Interventions: Drug: Dichloroacetate (DCA)
Genetic: Genetic Marker on Chromosome 14q24.3

Registration Number: NCT00874276

Lead Sponsor: University of Florida

Brief Summary: To establish the relationship between human MAAI haplotype and DCA and tyrosine metabolism. This aim test the postulates that MAAI haplotype determines, and thus can predict,1) dose-dependent DCA kinetics and biotransformation.

Detailed Description: The arms of the study involves determining the haplotype of individuals enrolled. Then participants were divided into two groups based on their genotype. The groups include a genotype with an EGT alle and a group of genotype without an EGT alle. All subjects first took a low dose of DCA 2.5ug/kg for 5 days then wait 30 days and take a therapeutic dose of DCA 25mg/kg for 5 days On the first day and on the 5th day of taking DCA kinetics were be done. A total of 16 blood samples were obtained through an intravenous catheter. Urine collection will also occur.

Population pharmacogenetic analysis of MAI allelic frequencies and the GC or LC-MS/MS techniques for blood or urinary metabolites were used in this investigation. Pharmacokinetic data was used to determine metabolism rate of DCA for each allele

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 21

Inclusion Criteria

Healthy volunteers

Exclusion Criteria

Pregnancy
Other medications
Psychiatric illness on meds
Abnormal labs

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
No EGT Allele, slow metabolizers for DCA	Dichloroacetate (DCA)	Individuals were genotyped at the beginning of the study and their haplotypes were defined. Dichloroacetate 2.5.ug/kg (non-clinical dose) will be administered for five days in the clinical research center. On day 5 with the dose of DCA a pharmacokinetics test will be performed for 24 hours. 30 days later the individuals will return to the clinic and receive Dichloroacetate 25mg/kg (clinical dose) for five days. On day 1 and day 5 Pharmacokinetics will be performed to determine the relationship between DCA metabolism and haplotype.
1+ EGT Allele, fast metabolizers for DCA	Dichloroacetate (DCA)	Individuals were genotyped at the beginning of the study and their haplotypes were defined. Dichloroacetate 2.5.ug/kg (non-clinical dose) will be administered for five days in the clinical research center. On day 5 with the dose of DCA a pharmacokinetics test will be performed for 24 hours. 30 days later the individuals will return to the clinic and receive Dichloroacetate 25mg/kg (clinical dose) for five days. On day 1 and day 5 Pharmacokinetics will be performed to determine the relationship between DCA metabolism and haplotype.
No EGT Allele, slow metabolizers for DCA	Genetic Marker on Chromosome 14q24.3	Individuals were genotyped at the beginning of the study and their haplotypes were defined. Dichloroacetate 2.5.ug/kg (non-clinical dose) will be administered for five days in the clinical research center. On day 5 with the dose of DCA a pharmacokinetics test will be performed for 24 hours. 30 days later the individuals will return to the clinic and receive Dichloroacetate 25mg/kg (clinical dose) for five days. On day 1 and day 5 Pharmacokinetics will be performed to determine the relationship between DCA metabolism and haplotype.
1+ EGT Allele, fast metabolizers for DCA	Genetic Marker on Chromosome 14q24.3	Individuals were genotyped at the beginning of the study and their haplotypes were defined. Dichloroacetate 2.5.ug/kg (non-clinical dose) will be administered for five days in the clinical research center. On day 5 with the dose of DCA a pharmacokinetics test will be performed for 24 hours. 30 days later the individuals will return to the clinic and receive Dichloroacetate 25mg/kg (clinical dose) for five days. On day 1 and day 5 Pharmacokinetics will be performed to determine the relationship between DCA metabolism and haplotype.

Primary Outcome Measures

Name	Time	Method
Hypothesize That Subject's Genotype Will Determine How DCA is Metabolized.	24 hours for analysis on Day 5, Clinical dose	Terminal half-life (the amount of time needed to clear one-half of dose of the drug).

Secondary Outcome Measures

Name	Time	Method
Terminal Half-life (the Amount of Time Needed to Clear One-half of the Dose of Drug)for Environmental Dose 2.5 ug/kg/Day.	24 hours for analysis on Day 5, Environmental dose	Terminal half-life (the amount of time needed to clear one-half of the dose of drug)for the environmental dose 2.5 ug/kg/day.