| Development of PBPK model of molinate and molinate sulfoxide in rats and humans. | |
| | |
MedLine Citation:
|
PMID: 19545510 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Molinate has been widely used as a pre-emergent herbicide in the rice fields of California's Central Valley. In rat studies, the metabolite molinate sulfoxide is suspected of causing testicular toxicity after exposure to molinate. The sulfoxide is generated in the liver and can circulate in the blood, eventually reaching the testis. Man qualitatively produces the same molinate metabolites as the rat. To extrapolate the reproductive risk to man, the present study outlines the development of a preliminary PBPK (physiologically-based pharmacokinetic) model, validation in the rat and extrapolation to man. The preliminary seven-compartment PBPK model for molinate was constructed for the adult, male Sprague-Dawley rat that employed both flow-limited (blood, kidney, liver, rapid-perfused tissues and slowly perfused tissues) and diffusion-limited (fat) rate equations. The systemic circulation connects the various compartments. The simulations predict the molinate blood concentrations of the rat blood and testes compartment favorably with the profiles obtained from 10 and 100mg/kg po or 1.5 and 15mg/kg iv doses. Human physiological parameters were substituted into the oral dosed model and the simulations closely predicted the molinate blood concentration obtained from 5.06mg oral dose. A sensitivity analysis determined for an oral dose that peak blood molinate concentrations were most responsive to the blood flows to kidney and fat compartments while testicular molinate sulfoxide concentrations depended on molinate sulfoxide partition coefficients for the testes compartment and the K(m) for glutathione conjugation of molinate sulfoxide in the liver compartment. |
| | |
Authors:
|
Andrew Campbell |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-01-23 |
Journal Detail:
|
Title: Regulatory toxicology and pharmacology : RTP Volume: 53 ISSN: 1096-0295 ISO Abbreviation: Regul. Toxicol. Pharmacol. Publication Date: 2009 Apr |
Date Detail:
|
Created Date: 2010-06-10 Completed Date: 2010-11-03 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 8214983 Medline TA: Regul Toxicol Pharmacol Country: United States |
Other Details:
|
Languages: eng Pagination: 195-204 Citation Subset: IM |
Affiliation:
|
Department of Environmental Toxicology, UC Davis, Davis, CA 95616, USA. arc40@astound.net |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Administration, Oral Animals Azepines / blood, pharmacokinetics*, toxicity Dose-Response Relationship, Drug Herbicides / blood, pharmacokinetics*, toxicity Humans Injections, Intravenous Kidney / metabolism, physiology Liver / metabolism, physiology Male Models, Biological* Molecular Structure Physiological Phenomena* Predictive Value of Tests Rats Rats, Sprague-Dawley Species Specificity Sulfoxides / blood, pharmacokinetics*, toxicity Testis / drug effects, metabolism, physiology Thiocarbamates / blood, pharmacokinetics*, toxicity Tissue Distribution |
| Grant Support | |
ID/Acronym/Agency:
|
5-T32-EOS- 7059//PHS HHS; T35 ES007301-12/ES/NIEHS NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/Azepines; 0/Herbicides; 0/Sulfoxides; 0/Thiocarbamates; 0/molinate sulfoxide; 2212-67-1/molinate |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Proteomics tools and resources for investigating protein allergens in oilseeds.
Next Document: Reconstruction of Historical Exposures in the U.S. Nickel Alloy Industry and the Implications for Ca...