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    Physiological Models

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    Kavita Sekar
    This document summarizes physiological models used to model drug disposition in the body. It describes two types of physiological models: 1) blood flow rate-limited models that are commonly used for highly permeable drugs where movement within tissues is faster than blood delivery, and 2) membrane permeation rate-limited models that are more complex and used for drugs where the cell membrane limits diffusion. The models can predict drug concentrations in tissues based on organ size, blood flow rates, and tissue-blood partition coefficients without data fitting. However, obtaining experimental data to parameterize the models is exhaustive.

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    Physiological Models

    Uploaded by

    Kavita Sekar
    77 views4 pages
    This document summarizes physiological models used to model drug disposition in the body. It describes two types of physiological models: 1) blood flow rate-limited models that are commonly used for highly permeable drugs where movement within tissues is faster than blood delivery, and 2) membrane permeation rate-limited models that are more complex and used for drugs where the cell membrane limits diffusion. The models can predict drug concentrations in tissues based on organ size, blood flow rates, and tissue-blood partition coefficients without data fitting. However, obtaining experimental data to parameterize the models is exhaustive.

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    This document summarizes physiological models used to model drug disposition in the body. It describes two types of physiological models: 1) blood flow rate-limited models that are commonly used for highly permeable drugs where movement within tissues is faster than blood delivery, and 2) membrane permeation rate-limited models that are more complex and used for drugs where the cell membrane limits diffusion. The models can predict drug concentrations in tissues based on organ size, blood flow rates, and tissue-blood partition coefficients without data fitting. However, obtaining experimental data to parameterize the models is exhaustive.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    77 views4 pages

    Physiological Models

    Uploaded by

    Kavita Sekar
    This document summarizes physiological models used to model drug disposition in the body. It describes two types of physiological models: 1) blood flow rate-limited models that are commonly used for highly permeable drugs where movement within tissues is faster than blood delivery, and 2) membrane permeation rate-limited models that are more complex and used for drugs where the cell membrane limits diffusion. The models can predict drug concentrations in tissues based on organ size, blood flow rates, and tissue-blood partition coefficients without data fitting. However, obtaining experimental data to parameterize the models is exhaustive.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
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    of 4

    PHYSIOLOGICAL MODELS

     These models are also known as physiologically-based pharmacokinetic models (PB-PK


    models).
     They are drawn on the basis of known anatomic and physiological data and thus present a
    more realistic picture of drug disposition in various organs and tissues.
     The number of compartments to be included in the model depends upon the disposition
    characteristics of the drug.

     Organs or tissues such as bones that have no drug penetration are excluded.
     Since describing each organ/tissue with mathematic equations makes the model complex,
    tissues with similar perfusion properties are grouped into a single compartment.
     For example, lungs, liver, brain and kidney are grouped as rapidly equilibrating tissues
    (RET) while muscles and adipose as slowly equilibrating tissues.

     Since the rate of drug carried to a tissue organ and tissue drug uptake are dependent upon
    two major factors –
     Rate of blood flow to the organ, and

     Tissue/blood partition coefficient or diffusion coefficient of drug that governs its


    tissue permeability,

     The physiological models are further categorized into two types


    1. Blood flow rate-limited models
     These models are more popular and commonly used than the second type, and are
    based on the assumption that the drug movement within a body region is much more
    rapid than its rate of delivery to that region by the perfusing blood.
     These models are therefore also called as perfusion rate-limited models.
     This assumption is however applicable only to the highly membrane permeable drugs
    i.e. low molecular weight, poorly ionised and highly lipophilic drugs, for example,
    thiopental, lidocaine, etc
    2. Membrane permeation rate-limited models
     These models are more complex and applicable to highly polar, ionised and charged
    drugs, in which case the cell membrane acts as a barrier for the drug that gradually
    permeates by diffusion.
     These models are therefore also called as diffusion-limited models.
     Owing to the time lag in equilibration between the blood and the tissue, equations
    for these models are very complicated.

    Q indicates blood flow rate to a body region. HPT stands for other highly perfused tissues and PPT for poorly
    perfused tissues. Km is rate constant for hepatic elimination and Ke is first-order rate constant for urinary
    excretion

    ADVANTAGES
     Mathematical treatment is straightforward.
     Since it is a realistic approach, the model is suitable where tissue drug concentration and
    binding are known.
     Data fitting is not required since drug concentration in various body regions can be
    predicted on the basis of organ or tissue size, perfusion rate and experimentally
    determined tissue-to-plasma partition coefficient.
     The model gives exact description of drug concentration-time profile in any organ or
    tissue and thus better picture of drug distribution characteristics in the body.
     The method is frequently used in animals because invasive methods can be used to
    collect tissue samples.
     Mechanism of ADME of drug can be easily explained by this model.

    DISADVANTAGES
     Obtaining the experimental data is a very exhaustive process.
     Most physiological models assume an average blood flow for individual subjects and
    hence prediction of individualized dosing is difficult.
     The number of data points is less than the pharmacokinetic parameters to be assessed.
     Monitoring of drug concentration in body is difficult since exhaustive data is required
    Physiologic Pharmacokinetic Model with Binding
     The physiologic pharmacokinetic model assumes flow-limited drug distribution without drug
    binding to either plasma or tissues.
     In reality, many drugs are bound to a variable extent in either plasma or tissues. With most
    physiologic models, drug binding is assumed to be linear (not saturable or concentration
    dependent).
     Moreover, bound and free drug in both tissue and plasma are in equilibrium. Further, the free
    drug in the plasma and in the tissue equilibrates rapidly.
     Therefore, the free drug concentration in the tissue and the free drug concentration in the
    emerging blood are equal:

    where f b is the blood free drug fraction, f t is the tissue free drug fraction, C t is the total drug
    concentration in tissue, and C b is the total drug concentration in blood.
     Therefore, the partition ratio, P t , of the tissue drug concentration to that of the plasma drug
    concentration is

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