Physiologically Based Pharmacokinetic Model of Methyl Tertiary Butyl Ether and Tertiary Butyl Alcohol Dosimetry in Male Rats Based on Binding to α2u-Globulin

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.