Effect of short-term drinking water exposure to dichloroacetate on its pharmacokinetics nd oral bioavailability in human volunteers: A stable isotope study

Irvin R. Schultz, Robert Shangraw

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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 (t1/2,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 AUC 0→∞ for both oral and iv DCAA doses (p <0.04 and p <0.014, respectively) with a corresponding decrease in the Clb.

Original languageEnglish (US)
Pages (from-to)42-50
Number of pages9
JournalToxicological Sciences
Volume92
Issue number1
DOIs
StatePublished - Jul 2006

Fingerprint

Dichloroacetic Acid
Pharmacokinetics
Isotopes
Drinking Water
Biological Availability
Volunteers
Area Under Curve

Keywords

  • Chlorination
  • GST-zeta
  • Haloacetic acids

ASJC Scopus subject areas

  • Toxicology

Cite this

@article{22e75eeefb5f4c0a9217215e7dceb760,
title = "Effect of short-term drinking water exposure to dichloroacetate on its pharmacokinetics nd oral bioavailability in human volunteers: A stable isotope study",
abstract = "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 (t1/2,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 AUC 0→∞ for both oral and iv DCAA doses (p <0.04 and p <0.014, respectively) with a corresponding decrease in the Clb.",
keywords = "Chlorination, GST-zeta, Haloacetic acids",
author = "Schultz, {Irvin R.} and Robert Shangraw",
year = "2006",
month = "7",
doi = "10.1093/toxsci/kfj193",
language = "English (US)",
volume = "92",
pages = "42--50",
journal = "Toxicological Sciences",
issn = "1096-6080",
publisher = "Oxford University Press",
number = "1",

}

TY - JOUR

T1 - Effect of short-term drinking water exposure to dichloroacetate on its pharmacokinetics nd oral bioavailability in human volunteers

T2 - A stable isotope study

AU - Schultz, Irvin R.

AU - Shangraw, Robert

PY - 2006/7

Y1 - 2006/7

N2 - 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 (t1/2,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 AUC 0→∞ for both oral and iv DCAA doses (p <0.04 and p <0.014, respectively) with a corresponding decrease in the Clb.

AB - 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 (t1/2,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 AUC 0→∞ for both oral and iv DCAA doses (p <0.04 and p <0.014, respectively) with a corresponding decrease in the Clb.

KW - Chlorination

KW - GST-zeta

KW - Haloacetic acids

UR - http://www.scopus.com/inward/record.url?scp=33745627047&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745627047&partnerID=8YFLogxK

U2 - 10.1093/toxsci/kfj193

DO - 10.1093/toxsci/kfj193

M3 - Article

C2 - 16611621

AN - SCOPUS:33745627047

VL - 92

SP - 42

EP - 50

JO - Toxicological Sciences

JF - Toxicological Sciences

SN - 1096-6080

IS - 1

ER -