This article is available online at http://dmd.aspetjournals.org
ABSTRACT:Trichloroacetic acid (TCA), a mouse liver carcinogen, is a drinking water contaminant and a metabolite of solvents such as trichloroethylene and perchloroethylene. Because acidic drugs are often bound more strongly to human than to rodent plasma proteins, a study was undertaken to determine whether this was the case for TCA and to clarify the mechanistic bases for species differences. Equilibrium dialysis was used to measure in vitro binding of a range of TCA concentrations to plasma of humans, rats, and mice. Plots of observed data for free versus bound TCA concentrations were compared with simulations from each of three binding models: a single saturable site model; a saturable plus nonsaturable site model; and a two-saturable site model. Dissociation values (K d ) did not differ significantly from one species to another, but N (number of binding sites/molecule) ranged from 2.97 for humans to 0.17 for mice. Binding capacities (B max ) for humans, rats, and mice were 709, 283, and 29 M, respectively. The greater plasma protein binding of TCA in humans would be expected to not only increase the residence time of the compound in the bloodstream, but to substantially reduce the proportion of TCA that is available for uptake by the liver and other tissues. Species differences in the bound fraction diminished at very low, environmentally relevant TCA concentrations, but the percentage bound increased markedly. These findings suggest that the practice of using total blood levels of TCA as a dose metric in interspecies extrapolation of cancer risks needs to be re-examined.
Benzo[a]pyrene (BaP) is a by-product of incomplete combustion of fossil fuels and plant/wood products, including tobacco. A physiologically based pharmacokinetic (PBPK) model for BaP for the rat was extended to simulate inhalation exposures to BaP in rats and humans including particle deposition and dissolution of absorbed BaP and renal elimination of 3-hydroxy benzo[a]pyrene (3-OH BaP) in humans. The clearance of particle-associated BaP from lung based on existing data in rats and dogs suggest that the process is bi-phasic. An initial rapid clearance was represented by BaP released from particles followed by a slower first-order clearance that follows particle kinetics. Parameter values for BaP-particle dissociation were estimated using inhalation data from isolated/ventilated/perfused rat lungs and optimized in the extended inhalation model using available rat data. Simulations of acute inhalation exposures in rats identified specific data needs including systemic elimination of BaP metabolites, diffusion-limited transfer rates of BaP from lung tissue to blood and the quantitative role of macrophage-mediated and ciliated clearance mechanisms. The updated BaP model provides very good prediction of the urinary 3-OH BaP concentrations and the relative difference between measured 3-OH BaP in nonsmokers versus smokers. This PBPK model for inhaled BaP is a preliminary tool for quantifying lung BaP dosimetry in rat and humans and was used to prioritize data needs that would provide significant model refinement and robust internal dosimetry capabilities.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.