Effect of Short-Term Drinking Water Exposure to Dichloroacetate on its Pharmacokinetics and Oral Bioavailability in Human Volunteers: A Stable Isotope Study

Dichloroacetic acid (DCAA) is a by-product of drinking water disinfection, is 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 (eight men, eight women) 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 consumed 12C-DCAA (2 mg/kg) dissolved in 500 ml water over a period of 3 min. Five minutes after the start of the 12C-DCAA consumption, 13C-labeled DCAA (0.3 mg/kg) was administered iv over 20 s and plasma 12C/13C-DCAA concentrations measured at predetermined time points over 4 h. Volunteers subsequently consumed for 14 consecutive days DCAA 0.02 μg/kg/day dissolved in 500 ml water to simulate a low-level chronic DCAA intake. Afterward, the 12C/13C-DCAA administrations were repeated. Study end points were calculation of AUC0→∞, apparent volume of distribution (Vss), total body clearance (Clb), plasma elimination half-life (t½,β), 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 interindividual variation, ranging from 27 to 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 more rapidly (increased Ka), and cleared DCAA more slowly (decreased Clb), than men. Only women were affected by previous 14-day DCAA exposure, which increased the AUC0→∞ for both oral and iv DCAA doses (p < 0.04 and p < 0.014, respectively) with a corresponding decrease in the Clb.