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ToxSci Advance Access first published online on March 6, 2009
This version published online on April 15, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp049
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Physiologically Based Pharmacokinetic Model of Methyl tertiary Butyl Ether and tertiary Butyl Alcohol Dosimetry in Male Rats Based on Binding to {alpha}2u-Globulin

Teresa L. Leavens*,{dagger} and Susan J. Borghoff*,{dagger}{dagger},**

* Formerly The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina, 27709 {dagger} Center for Chemical Toxicology Research and Pharmacokinetics, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, 27606; email:teresa_leavens{at}ncsu.edu {dagger}{dagger} Integrated Laboratory Systems Inc, Research Triangle Park, North Carolina, 27709; email: sborghoff{at}ils-inc.com

** To whom correspondence should be addressed: Susan J. Borghoff, Integrated Laboratory Systems Inc, 601 Keystone Park Drive, Suite 100, Durham, NC 27713; email: sborghoff{at}ils-inc.com; Phone: (919).281-1110 ext 717; Fax: (919).281-1118

Received December 18, 2008; revision received February 28, 2009; accepted March 2, 2009


  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 {alpha}2u-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 {alpha}2u-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 {alpha}2u-globulin was modeled as saturable and competitive and was assumed to only affect the rate of hydrolysis of {alpha}2u-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 {alpha}2u-globulin was greater than TBA, and the hydrolysis rate of chemically bound {alpha}2u-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 {alpha}2u-globulin as essential for predicting concentrations of these chemicals in the kidney following exposure

Key Words: MTBE; TBA; {alpha}2u-globulin; PBPK.


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