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    Multicompartment Models: Prof. Dr. Henny Lucida, Apt

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    reymon taro
    The document describes multicompartment models used to explain drug distribution kinetics observed after intravenous injection. A two-compartment open model is presented where the drug distributes into a central and peripheral compartment and transfer between compartments follows first-order kinetics. The method of residuals is described to calculate model parameters from plasma concentration-time data by determining slopes for distribution (a) and elimination (b) processes. An example application to experimental data is provided to illustrate the method.

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    Multicompartment Models: Prof. Dr. Henny Lucida, Apt

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    reymon taro
    49 views13 pages
    The document describes multicompartment models used to explain drug distribution kinetics observed after intravenous injection. A two-compartment open model is presented where the drug distributes into a central and peripheral compartment and transfer between compartments follows first-order kinetics. The method of residuals is described to calculate model parameters from plasma concentration-time data by determining slopes for distribution (a) and elimination (b) processes. An example application to experimental data is provided to illustrate the method.

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    The document describes multicompartment models used to explain drug distribution kinetics observed after intravenous injection. A two-compartment open model is presented where the drug distributes into a central and peripheral compartment and transfer between compartments follows first-order kinetics. The method of residuals is described to calculate model parameters from plasma concentration-time data by determining slopes for distribution (a) and elimination (b) processes. An example application to experimental data is provided to illustrate the method.

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    49 views13 pages

    Multicompartment Models: Prof. Dr. Henny Lucida, Apt

    Uploaded by

    reymon taro
    The document describes multicompartment models used to explain drug distribution kinetics observed after intravenous injection. A two-compartment open model is presented where the drug distributes into a central and peripheral compartment and transfer between compartments follows first-order kinetics. The method of residuals is described to calculate model parameters from plasma concentration-time data by determining slopes for distribution (a) and elimination (b) processes. An example application to experimental data is provided to illustrate the method.

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    Multicompartment Models

    Prof. Dr. Henny Lucida, Apt


    These models were developed to explain
    the observation that, after a rapid IV
    injection, the Cp vs t curve does not
    decline linearly as a single, first order
    process.
    The drug distributes at various rates into
    different tissue groups. After drug
    equilibration within the peripheral tissues,
    the Cp vs t curve reflects first-order
    elimination of the drug from the body
    General Groupin of Tissues
    according to Blood Supply
    Blood Supply Tissue Group % BW

    Highly Heart, brain, hepatic-portal 9


    perfused system, kidney and
    endocrine glands
    Skin and muscle 50
    Adipose (fat) tissue & 19
    marrow
    Slowly Bone, ligaments, tendons, 22
    perfused cartilage, teeth and hair
    Two-Compartment open model
    • The plasma drug concentration declines
    biexponentially as the sum of two first-
    order processes– distribution and
    elimination.
    • The drug distributes into 2 comp: the
    central comp and the tissue (peripheral)
    comps. Drug transfer between the two
    comps is assumed to take place by first-
    order process.
    Basic Equations
     at  bt
    C p  Ae  Be
    D0 a  k 21 
    A
    V p a  b 
    D0 k 21  b 
    B
    V p a  b 
    a  b  k12  k 21  k
    a  b  k 21  k
    Residual Method
    Example:
    100 mg of a drug was administered by
    rapid IV injection to a 70-kg, healthy adult
    male. Blood samples were taken
    periodically after the administration of
    drug, and the plasma fraction of each
    sample was assayed for drug. The
    following data were obtained:
    Time Cp (mg/mL) Time Cp (mg/mL)
    (hr) (hr)
    0.25 43.00 4.0 6.50

    0.5 32.00 8.0 2.80

    1.0 20.00 12.0 1.20

    1.5 14.00 16.0 0.52

    2.0 11.00
    Step1. Transform data to log Cp

    Time Log Cp Time Log Cp


    (hr) (hr)
    0.25 1.6335 4.0 0.8129

    0.5 1.5051 8.0 0.4472

    1.0 1.3010 12.0 0.0792

    1.5 1.1461 16.0 -0.2840

    2.0 1.0414
    Plot log Cp vs time

    b
    Step 2. Determine the linear regression of line b
    (after 4 hr), these data represent only the
    elimination process thus the slopeof line is equal
    to K
    C p  Be  bt
    bt
    logC p  logB 
    2.303
    The linear regression:
    Y1=1.1785 – 0.0915 X1 (r=-0.9999)
    Slope = -0.0915; b = 0.2107/hr
    B=antilog 1.1785= 15.0834 mg/mL
    Equation for b : Cp = 15.08 e-0.21t
    Step 3. The ka is determined residually by subtracting the data point at
    < 4 hr with the fitted data using linear regression of b.
    At these data point, the absorption process is predominant, then the
    slope would be the ka.
    This step would be easily solved by using a semi-logarithmic paper.
    Then the linear regression of the subtracted data is determined:
    Y2 = 1.6727 – 0.8055 X2
    The slope = -0.8055, then a or ka = 1.8551/hr
    The intercept = 1.6727, then A or the C0 = antilog 1.6727 = 47.0652
    mg/mL.
    Equation for a : Cp = 47.06 e-1.85t
    Thus the profile of plasma conc based on two compartment model is

    Cp = 47.06 e-1.85t + 15.08 e-0.21t

    Then: k, k12 and k21 can be calculated.


    Problems
    A drug was administered by rapid iv injection
    into a 70-kg adult male. Blood samples
    were withdrawn over a 7-hour period and
    assayed for intact drug. The results are
    tabulated below. Using the method of
    residuals, calculate the values for
    intercepts A and B and slopes a, b, k, k12
    and k21.
    Time (hr) Cp (mg/mL) Time (hr) Cp (mg/mL)
    0.00 70.0 2.5 14.3
    0.25 53.8 3.0 12.6
    0.50 43.3 4.0 10.5
    0.75 35.0 5.0 9.0
    1.00 29.1 6.0 8.0
    1.50 21.2 7.0 7.0
    2.00 17.0

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