PNNL

Abstract

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??, apparent volume of distribution (Vss), total body clearance (Clb), plasma elimination half-life (t½,?), 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 28 – 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