ToxSci Advance Access originally published online on March 6, 2009
Toxicological Sciences 2009 109(2):321-335; doi:10.1093/toxsci/kfp049
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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 
2u-Globulin
,1,2
* Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709
Center for Chemical Toxicology Research and Pharmacokinetics, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27606
Integrated Laboratory Systems, Inc., Research Triangle Park, North Carolina 27709
2 To whom correspondence should be addressed at Integrated Laboratory Systems, Inc., 601 Keystone Park Drive, Suite 100, Durham, NC 27713. Fax: (919) 281-1118. E-mail: sborghoff{at}ils-inc.com.
Received December 18, 2008; accepted March 2, 2009
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Abstract |
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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 
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 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 2u-globulin was modeled as saturable and competitive and was assumed to only affect the rate of hydrolysis of 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 2u-globulin was greater than TBA, and the hydrolysis rate of chemically bound 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 2u-globulin as essential for predicting concentrations of these chemicals in the kidney following exposure.
Key Words: MTBE; TBA; 2u-globulin; PBPK.
1 Present address: Center for Chemical Toxicology Research and Pharmacokinetics, Department Population Health and Pathobiology, College of Veterinary Medicine, NC State University, Raleigh, NC 27606.