Pharmacotoxicology of Trichloroethylene Metabolites

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

• Dichloroacetate (DCA) (Drug), also known as genotype: Dichloroacetate 2.5.ug/kg 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.
• Genetic Marker on Chromosome 14q24.3 (Genetic), also known as Genetic Marker, Haplotypes: Individuals were genotyped at the beginning of the study and their haplotypes were defined. The study is looking at individuals with genetic markers on Chromosome 14q24.3 to determine if there will be a difference in how the DCA will be metabolized.

Primary outcomes

• 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 outcomes

• 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.

Sex: All, ages: 21 Years to 50 Years, accepts healthy volunteers

Inclusion Criteria:

* Healthy volunteers

Exclusion Criteria:

* Pregnancy
* Other medications
* Psychiatric illness on meds
* Abnormal labs

Participant flow

Outcome results

• Hypothesize That Subject's Genotype Will Determine How DCA is Metabolized. (Primary), Median, Minutes: Lack Any EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 1592 (727 to 1774); 1+ EGT Allele on GSTz1/MAAI Region of Chromosome 14q24.3 232 (126 to 310) (p 0.023)
• 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. (Secondary), Median, minutes: No EGT Allele 65.4 (56.3 to 66.4); At Least One EGT Allele 74.3 (58.9 to 90.4) (p 0.42)

Adverse events

Time frame: Adverse events were collected from 5/2008 to 2/2009

Serious adverse events by term

Other adverse events by term

• Peter W Stacpoole, PhD, MD, Principal investigator, University of Florida