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An approach for incorporating tissue composition data into physiologically based pharmacokinetic models

M Pelekis1, P Poulin, K Krishnan

  • 1Département de médecine du travail et d'hygiène du milieu, Faculté de médecine, Université de Montréal, Canada.

Toxicology and Industrial Health
|September 1, 1995
PubMed
Summary

This study developed a new method for physiologically based pharmacokinetic (PBPK) models by incorporating tissue composition. This approach improves the calculation of tissue: air partition coefficients (PCs) for volatile organic chemicals, enhancing risk assessments.

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Area of Science:

  • Pharmacokinetics and Toxicokinetics
  • Physiologically Based Pharmacokinetic (PBPK) Modeling
  • Environmental Health and Toxicology

Background:

  • Conventional physiologically based pharmacokinetic (PBPK) models often treat tissue compartments as inert spaces.
  • Accurate calculation of tissue: air partition coefficients (PCs) is crucial for understanding volatile organic chemical (VOC) pharmacokinetics.
  • Incorporating detailed tissue composition can enhance the biological relevance of PBPK models.

Purpose of the Study:

  • To develop an approach for integrating tissue composition data into PBPK models.
  • To enable the "built-in" calculation of tissue: air partition coefficients (PCs) for VOCs.
  • To improve the biological basis and accuracy of PBPK models for risk assessment.

Main Methods:

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  • Characterized PBPK model tissue compartments as mixtures of lipids and water.
  • Automated calculation of tissue solubility using n-octanol and water solubility data.
  • Estimated tissue: air PCs by dividing tissue solubility by vapor concentration at 37°C.
  • Incorporated human tissue composition data (lipids, water) into PBPK models.
  • Calculated tissue: air PCs for dichloromethane (DCM) in human tissues and simulated DCM pharmacokinetics.

    • Main Results:

    • The developed approach successfully calculated tissue: air PCs within PBPK models.
    • Predicted human tissue: air PC values were comparable to rat-derived values when tissue composition was similar.
    • The study highlighted potential discrepancies when extrapolating rat-derived PCs to human tissues like muscle.
    • Interindividual variations in tissue composition significantly impact tissue dose, potentially not fully captured by blood concentrations.
    • The PBPK modeling demonstrated that venous blood concentrations may not adequately reflect interindividual differences in tissue dose.

    Conclusions:

    • Incorporating tissue composition into PBPK models enhances their biological foundation.
    • This approach provides a method to evaluate the impact of tissue composition variability on risk assessment.
    • The findings suggest caution when assuming rat tissue: air PCs are directly applicable to human PBPK models.
    • The study underscores the importance of species-specific and interindividual tissue composition data in PBPK modeling.
    • This method improves the accuracy of tissue dose surrogates used in PBPK-based risk assessments.