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Physiologically based pharmacokinetic model of methyl tertiary butyl ether and tertiary butyl alcohol dosimetry in male rats based on binding to alpha2u-globulin.
Toxicol Sci. 2009 Jun; 109(2):321-35.TS

Abstract

Current physiologically based pharmacokinetic (PBPK) models for the fuel additive methyl tertiary butyl ether (MTBE) and its metabolite tertiary butyl alcohol (TBA) have not included a mechanism for chemical binding to the male rat-specific protein alpha2u-globulin, which has been postulated to be responsible for renal effects in male rats observed in toxicity and carcinogenicity studies with MTBE. The objective of this work was to expand the previously published models for MTBE to include binding to alpha2u-globulin in the kidney of male rats. In the model, metabolism of MTBE was assumed to occur only in the liver via two saturable pathways. TBA metabolism was assumed to occur only in the liver via one saturable, low-affinity pathway and to be inducible following repeated exposures. The binding of MTBE and TBA to alpha2u-globulin was modeled as saturable and competitive and was assumed to only affect the rate of hydrolysis of alpha2u-globulin in the kidney. The developed model characterized the differences in kidney concentrations of MTBE and TBA in male versus female rats from inhalation exposures to MTBE, as well as the observed changes in blood and tissue concentrations from repeated exposure to TBA. The model-predicted binding affinity of MTBE to alpha2u-globulin was greater than TBA, and the hydrolysis rate of chemically bound alpha2u-globulin was approximately 30% of the unbound protein. This PBPK model supports the role of MTBE and TBA binding to the male rat-specific protein alpha2u-globulin as essential for predicting concentrations of these chemicals in the kidney following exposure.

Authors+Show Affiliations

Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19270017

Citation

Leavens, Teresa L., and Susan J. Borghoff. "Physiologically Based Pharmacokinetic Model of Methyl Tertiary Butyl Ether and Tertiary Butyl Alcohol Dosimetry in Male Rats Based On Binding to Alpha2u-globulin." Toxicological Sciences : an Official Journal of the Society of Toxicology, vol. 109, no. 2, 2009, pp. 321-35.
Leavens TL, Borghoff SJ. Physiologically based pharmacokinetic model of methyl tertiary butyl ether and tertiary butyl alcohol dosimetry in male rats based on binding to alpha2u-globulin. Toxicol Sci. 2009;109(2):321-35.
Leavens, T. L., & Borghoff, S. J. (2009). Physiologically based pharmacokinetic model of methyl tertiary butyl ether and tertiary butyl alcohol dosimetry in male rats based on binding to alpha2u-globulin. Toxicological Sciences : an Official Journal of the Society of Toxicology, 109(2), 321-35. https://doi.org/10.1093/toxsci/kfp049
Leavens TL, Borghoff SJ. Physiologically Based Pharmacokinetic Model of Methyl Tertiary Butyl Ether and Tertiary Butyl Alcohol Dosimetry in Male Rats Based On Binding to Alpha2u-globulin. Toxicol Sci. 2009;109(2):321-35. PubMed PMID: 19270017.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Physiologically based pharmacokinetic model of methyl tertiary butyl ether and tertiary butyl alcohol dosimetry in male rats based on binding to alpha2u-globulin. AU - Leavens,Teresa L, AU - Borghoff,Susan J, Y1 - 2009/03/06/ PY - 2009/3/10/entrez PY - 2009/3/10/pubmed PY - 2009/9/4/medline SP - 321 EP - 35 JF - Toxicological sciences : an official journal of the Society of Toxicology JO - Toxicol Sci VL - 109 IS - 2 N2 - Current physiologically based pharmacokinetic (PBPK) models for the fuel additive methyl tertiary butyl ether (MTBE) and its metabolite tertiary butyl alcohol (TBA) have not included a mechanism for chemical binding to the male rat-specific protein alpha2u-globulin, which has been postulated to be responsible for renal effects in male rats observed in toxicity and carcinogenicity studies with MTBE. The objective of this work was to expand the previously published models for MTBE to include binding to alpha2u-globulin in the kidney of male rats. In the model, metabolism of MTBE was assumed to occur only in the liver via two saturable pathways. TBA metabolism was assumed to occur only in the liver via one saturable, low-affinity pathway and to be inducible following repeated exposures. The binding of MTBE and TBA to alpha2u-globulin was modeled as saturable and competitive and was assumed to only affect the rate of hydrolysis of alpha2u-globulin in the kidney. The developed model characterized the differences in kidney concentrations of MTBE and TBA in male versus female rats from inhalation exposures to MTBE, as well as the observed changes in blood and tissue concentrations from repeated exposure to TBA. The model-predicted binding affinity of MTBE to alpha2u-globulin was greater than TBA, and the hydrolysis rate of chemically bound alpha2u-globulin was approximately 30% of the unbound protein. This PBPK model supports the role of MTBE and TBA binding to the male rat-specific protein alpha2u-globulin as essential for predicting concentrations of these chemicals in the kidney following exposure. SN - 1096-0929 UR - https://www.unboundmedicine.com/medline/citation/19270017/Physiologically_based_pharmacokinetic_model_of_methyl_tertiary_butyl_ether_and_tertiary_butyl_alcohol_dosimetry_in_male_rats_based_on_binding_to_alpha2u_globulin_ L2 - https://academic.oup.com/toxsci/article-lookup/doi/10.1093/toxsci/kfp049 DB - PRIME DP - Unbound Medicine ER -