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Development of physiologically based pharmacokinetic model for methyl tertiary-butyl ether and tertiary-butanol in male Fisher-344 rats.
Fundam Appl Toxicol. 1996 Apr; 30(2):264-75.FA

Abstract

Methyl tertiary-butyl ether (MTBE) and its metabolite tertiary-butanol (TBA) both cause renal tumors in chronically exposed male rats. Knowledge of the kinetic behavior of MTBE and TBA in rats and its comparison to the kinetics of these chemicals in humans will aid in assessing human risk. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for MTBE and TBA in rats that will form the basis for a human model. Physiological parameters such as blood flows, tissue volumes, and alveolar ventilation were obtained from the literature. Chemical-specific parameters such as the solubility of MTBE and TBA in blood and selected tissues and metabolic rate constants to describe whole-body metabolism of MTBE in rats were measured using vial equilibration and gas uptake techniques, respectively. MTBE metabolism was described in the model as occurring through two saturable pathways. The model was able to predict gas uptake data (100 to 2000 ppm starting concentrations) and levels of MTBE in blood of rats exposed to MTBE by inhalation (400 to 8000 ppm, 6 hr), i.v. (40 mg/kg), and oral (40 or 400 mg/kg) administration. Two different models to describe the dosimetry of TBA in a rat were tested for their ability to predict TBA blood levels after MTBE exposure. TBA blood levels were predicted best at low MTBE exposure concentrations using a two-compartment model. The pharmacokinetics of TBA appear to be far more complex than those of MTBE, and additional experimental data on TBA distribution and elimination will be necessary to refine the submodel. With a quantitative description of the important determinants of MTBE and TBA dosimetry understood, a better assessment of the potential toxic and cancer risk for humans exposed to MTBE can be made.

Authors+Show Affiliations

Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

8812274

Citation

Borghoff, S J., et al. "Development of Physiologically Based Pharmacokinetic Model for Methyl Tertiary-butyl Ether and Tertiary-butanol in Male Fisher-344 Rats." Fundamental and Applied Toxicology : Official Journal of the Society of Toxicology, vol. 30, no. 2, 1996, pp. 264-75.
Borghoff SJ, Murphy JE, Medinsky MA. Development of physiologically based pharmacokinetic model for methyl tertiary-butyl ether and tertiary-butanol in male Fisher-344 rats. Fundam Appl Toxicol. 1996;30(2):264-75.
Borghoff, S. J., Murphy, J. E., & Medinsky, M. A. (1996). Development of physiologically based pharmacokinetic model for methyl tertiary-butyl ether and tertiary-butanol in male Fisher-344 rats. Fundamental and Applied Toxicology : Official Journal of the Society of Toxicology, 30(2), 264-75.
Borghoff SJ, Murphy JE, Medinsky MA. Development of Physiologically Based Pharmacokinetic Model for Methyl Tertiary-butyl Ether and Tertiary-butanol in Male Fisher-344 Rats. Fundam Appl Toxicol. 1996;30(2):264-75. PubMed PMID: 8812274.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Development of physiologically based pharmacokinetic model for methyl tertiary-butyl ether and tertiary-butanol in male Fisher-344 rats. AU - Borghoff,S J, AU - Murphy,J E, AU - Medinsky,M A, PY - 1996/4/1/pubmed PY - 1996/4/1/medline PY - 1996/4/1/entrez SP - 264 EP - 75 JF - Fundamental and applied toxicology : official journal of the Society of Toxicology JO - Fundam Appl Toxicol VL - 30 IS - 2 N2 - Methyl tertiary-butyl ether (MTBE) and its metabolite tertiary-butanol (TBA) both cause renal tumors in chronically exposed male rats. Knowledge of the kinetic behavior of MTBE and TBA in rats and its comparison to the kinetics of these chemicals in humans will aid in assessing human risk. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for MTBE and TBA in rats that will form the basis for a human model. Physiological parameters such as blood flows, tissue volumes, and alveolar ventilation were obtained from the literature. Chemical-specific parameters such as the solubility of MTBE and TBA in blood and selected tissues and metabolic rate constants to describe whole-body metabolism of MTBE in rats were measured using vial equilibration and gas uptake techniques, respectively. MTBE metabolism was described in the model as occurring through two saturable pathways. The model was able to predict gas uptake data (100 to 2000 ppm starting concentrations) and levels of MTBE in blood of rats exposed to MTBE by inhalation (400 to 8000 ppm, 6 hr), i.v. (40 mg/kg), and oral (40 or 400 mg/kg) administration. Two different models to describe the dosimetry of TBA in a rat were tested for their ability to predict TBA blood levels after MTBE exposure. TBA blood levels were predicted best at low MTBE exposure concentrations using a two-compartment model. The pharmacokinetics of TBA appear to be far more complex than those of MTBE, and additional experimental data on TBA distribution and elimination will be necessary to refine the submodel. With a quantitative description of the important determinants of MTBE and TBA dosimetry understood, a better assessment of the potential toxic and cancer risk for humans exposed to MTBE can be made. SN - 0272-0590 UR - https://www.unboundmedicine.com/medline/citation/8812274/Development_of_physiologically_based_pharmacokinetic_model_for_methyl_tertiary_butyl_ether_and_tertiary_butanol_in_male_Fisher_344_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0272059096900640 DB - PRIME DP - Unbound Medicine ER -