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Titolo:
A physiologically based pharmacokinetic model for methyl tert-butyl ether in humans: Implementing sensitivity and variability analyses
Autore:
Licata, AC; Dekant, W; Smith, CE; Borghoff, SJ;
Indirizzi:
CIIT, Ctr Hlth Res, Res Triangle Pk, NC 27709 USA CIIT Res Triangle Pk NCUSA 27709 Hlth Res, Res Triangle Pk, NC 27709 USA N Carolina State Univ, Dept Stat, Biomath Grad Program, Raleigh, NC 27695 USA N Carolina State Univ Raleigh NC USA 27695 Program, Raleigh, NC 27695 USA Univ Wurzburg, Inst Toxikol, D-97078 Wurzburg, Germany Univ Wurzburg Wurzburg Germany D-97078 oxikol, D-97078 Wurzburg, Germany
Titolo Testata:
TOXICOLOGICAL SCIENCES
fascicolo: 2, volume: 62, anno: 2001,
pagine: 191 - 204
SICI:
1096-6080(200108)62:2<191:APBPMF>2.0.ZU;2-A
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN LIVER-MICROSOMES; REGULATORY RISK ANALYSIS; CYTOCHROMES P450; INTERINDIVIDUAL VARIABILITY; PARTITION-COEFFICIENTS; RATS; METABOLISM; EXPOSURE; MTBE; GASOLINE;
Keywords:
physiologically based pharmacokinetic (PBPK); model; methyl tert-butyl ether (MTBE); sensitivity analysis; variability analysis;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
46
Recensione:
Indirizzi per estratti:
Indirizzo: Borghoff, SJ CIIT, Ctr Hlth Res, 6 Davis Dr,POB 12137, Res Triangle Pk, NC27709 USA CIIT 6 Davis Dr,POB 12137 Res Triangle Pk NC USA 27709 09 USA
Citazione:
A.C. Licata et al., "A physiologically based pharmacokinetic model for methyl tert-butyl ether in humans: Implementing sensitivity and variability analyses", TOXICOL SCI, 62(2), 2001, pp. 191-204

Abstract

Methyl tert-butyl ether (MTBE) is added to gasoline to reduce carbon monoxide and ozone precursors from automobile emissions. The objectives of this study were to verify the ability of a physiologically based pharmacokinetic(PBPK) model to predict MTBE blood levels in humans and to investigate theeffect of variability in the metabolism of MTBE and its influence on the predicted MTBE blood levels. The model structure for MTBE was flow-limited and had six essential compartments: lung, liver, rapidly perfused tissues, slowly perfused tissues, fat, and kidney. In this model, two pathways of metabolism are described to occur in the liver by Michaelis-Menten kinetics. Metabolic rate constants were measured in vitro using human liver microsomesand extrapolated to in vivo whole-body metabolism. Model predictions were compared with data on blood levels of MTBE taken from humans during and after a 1-h inhalation exposure to 1.7 ppm MTBE and after 4-h inhalation exposures to 4 or 40 ppm MTBE. The PBPK model accurately predicted MTBE pharmacokinetics at the high and low MTBE exposure concentrations for all time points. At the intermediate MTBE exposure concentration, however, the model underpredicted early time points while adequately predicting later time points. Results of the sensitivity analysis indicated that the influence of metabolic parameters on model output was dependent on MTBE exposure concentration. Subsequent variability analysis indicated that there was more variability in the actual measured MTBE blood levels than in the blood levels predicted by the PBPK model when using the range of metabolic parameters measured in vitro in human liver samples. By incorporating an understanding of the metabolic processes, this PBPK model can be used to predict blood levels of MTBE, which is important in determining target tissue dose estimates for risk assessment.

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Documento generato il 04/04/20 alle ore 15:09:26