Document Detail


Blood concentrations of acrylonitrile in humans after oral administration extrapolated from in vivo rat pharmacokinetics, in vitro human metabolism, and physiologically based pharmacokinetic modeling.
MedLine Citation:
PMID:  20600458     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for acrylonitrile in humans based on in vitro metabolic parameters determined using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and a prior previously developed PBPK model in rats. The model basically consists of a chemical absorption compartment, a metabolizing compartment, and a central compartment for acrylonitrile. Evaluation of a previous rat model was performed by comparisons with experimental pharmacokinetic values from blood and urine obtained from rats in vivo after oral treatment with acrylonitrile (30 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of acrylonitrile in vitro were established using data from rat liver microsomes and from pooled human liver microsomes. Acrylonitrile was expected to be absorbed and cleared rapidly from the body in silico, as was the case for rats confirmed experimentally in vivo with repeated low-dose treatments. These results indicate that the simplified PBPK model for acrylonitrile is useful for a forward dosimetry approach in humans. This model may also be useful for simulating blood concentrations of other related compounds resulting from exposure to low chemical doses.
Authors:
Ryohji Takano; Norie Murayama; Kana Horiuchi; Masato Kitajima; Masatoshi Kumamoto; Fumiaki Shono; Hiroshi Yamazaki
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-06-23
Journal Detail:
Title:  Regulatory toxicology and pharmacology : RTP     Volume:  58     ISSN:  1096-0295     ISO Abbreviation:  Regul. Toxicol. Pharmacol.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-10-11     Completed Date:  2011-01-19     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8214983     Medline TA:  Regul Toxicol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  252-8     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
Affiliation:
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan.
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MeSH Terms
Descriptor/Qualifier:
Acrylonitrile / administration & dosage,  pharmacokinetics*
Administration, Oral
Animals
Dose-Response Relationship, Drug
Humans
Male
Microsomes, Liver / metabolism*
Models, Biological*
No-Observed-Adverse-Effect Level
Rats
Species Specificity
Chemical
Reg. No./Substance:
107-13-1/Acrylonitrile

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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