ToxSci Advance Access published online on April 12, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj193
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1 Battelle Pacific NW Division, Sequim, WA, 98382
* To whom correspondence should be addressed. Dichloroacetic acid (DCAA) is a by-product of drinking water disinfection, a known rodent hepatocarcinogen and is also used therapeutically to treat a variety of metabolic disorders in humans. We measured DCAA bioavailability in 16 human volunteers (8 male, 8 female) after simultaneous administration of oral and iv DCAA doses. Volunteers consumed DCAA-free bottled water for 2 weeks to wash out background effects of DCAA. Subsequently, each subject drank 12C-DCAA (2 mg /kg ) in 500 ml water over three minutes. Five minutes after the start of the 12C-DCAA consumption, 13C-labeled DCAA (0.3 mg/kg) was administered iv over 20 seconds, and plasma 12C/13C-DCAA concentrations measured at predetermined time points over 4 h. Volunteers subsequently consumed DCAA 0.02 mg/kg/day in 500 ml water for 14 consecutive days to simulate a low-level chronic DCAA intake. Afterwards, the 12C/13C-DCAA administrations was repeated. Study endpoints were calculation of AUC0
Received January 10, 2006
Accepted April 6, 2006
Biotransformation and Toxicokinetics
Effect of Short-Term Drinking Water Exposure to Dichloroacetate on its Pharmacokinetics and Oral Bioavailability in Human Volunteers: A Stable Isotope Study
Irvin R. Schultz 1 *
and
Robert E. Shangraw 2
2 Oregon Health Science University, Portland, OR, 97239-3098
Irvin R. Schultz, E-mail: ir_schultz{at}pnl.gov
Abstract 
, apparent volume of distribution (Vss), total body clearance (Clb), plasma elimination half-life (t
,
), oral absorption rate (Ka), and oral bioavailability. Oral bioavailability was estimated from dose-adjusted AUC ratios, and by using a compartmental pharmacokinetic model after simultaneous fitting of oral and iv DCAA concentration-time profiles. DCAA bioavailability had large inter-individual variation, ranging from 27 - 100%. In the absence of prior DCAA intake, there were no significant differences (p>0.05) in any pharmacokinetic parameters between male and female volunteers, although there was a trend that women absorbed DCAA was more rapidly (increased Ka), and cleared DCAA more slowly (decreased Clb), than men. Only women were affected by previous 14 d DCAA exposure, which increased the AUC0 for both oral and i.v. DCAA doses (P<0.04; 0.014 respectively) with a corresponding decrease in the Clb.
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