Physiologically based pharmacokinetic modelling: a sub-compartmentalized model of tissue distribution

Area of Science:

• Pharmacokinetics and Drug Metabolism
• Physiologically Based Pharmacokinetic Modeling
• Quantitative Systems Pharmacology

Background:

• Existing well-stirred tissue models simplify drug distribution.
• Accurate modeling of drug concentration in various tissue compartments is crucial for predicting drug behavior.
• Understanding tissue-specific drug distribution is essential for drug development and personalized medicine.

Purpose of the Study:

• To present a novel sub-compartmentalized model for drug distribution in tissues.
• To explicitly account for drug concentrations in erythrocytes, plasma, interstitial, and cellular spaces.
• To provide a transparent framework for constructing and parameterizing tissue distribution models for diverse drug chemistries.

Main Methods:

• Developed a sub-compartmentalized model specified by differential equations.
• Incorporated drug concentrations in erythrocytes, plasma, interstitial, and cellular spaces.
• Derived established models for tissue-plasma partition coefficients by assuming steady-state distribution and lumping sub-compartments.

Main Results:

• Successfully constructed and parameterized the sub-compartmentalized model for bases, acids, neutrals, and zwitterions.
• Demonstrated a simple derivation of tissue-plasma partition coefficients from the model.
• Highlighted the contributions of different tissue constituents to drug distribution.

Conclusions:

• The sub-compartmentalized model offers a more detailed and accurate representation of drug distribution than well-stirred models.
• The model provides a flexible and transparent framework for developing new tissue distribution models.
• This approach facilitates a deeper understanding of drug behavior within tissues, aiding in drug development and therapeutic strategies.