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Multi Compartment Models

Multi-compartment models account for the fact that different tissues distribute and eliminate drugs in non-linear ways. A multi-compartment model represents the body as a series of compartments that represent different tissues, with curves describing the transfer of drug between compartments. The most complex models, called PBPK models, use physiological data to model distribution and elimination. Non-linear pharmacokinetics can occur due to multi-phasic absorption, enzymatic saturation affecting metabolism, drug interactions that induce or inhibit metabolism, and active kidney elimination independent of plasma concentrations.

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58 views2 pages

Multi Compartment Models

Multi-compartment models account for the fact that different tissues distribute and eliminate drugs in non-linear ways. A multi-compartment model represents the body as a series of compartments that represent different tissues, with curves describing the transfer of drug between compartments. The most complex models, called PBPK models, use physiological data to model distribution and elimination. Non-linear pharmacokinetics can occur due to multi-phasic absorption, enzymatic saturation affecting metabolism, drug interactions that induce or inhibit metabolism, and active kidney elimination independent of plasma concentrations.

Uploaded by

vijay kumar honnali
Copyright
© © All Rights Reserved
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Multi-compartment models[edit]

Further information: Multi-compartment model

Graphs for absorption and elimination for a non-linear


pharmacokinetic model
In the real world, each tissue will have its own distribution characteristics and none of them will be
strictly linear. The two-compartment model may not be applicable in situations where some of the
enzymes responsible for metabolizing the drug become saturated, or where an active elimination
mechanism is present that is independent of the drug's plasma concentration. If we label the
drug's volume of distribution within the organism VdF and its volume of distribution in a tissue VdT the
former will be described by an equation that takes into account all the tissues that act in different
ways, that is:

This represents the multi-compartment model with a number of curves that express complicated
equations in order to obtain an overall curve. A number of computer programs have been
developed to plot these equations.[9] The most complex PK models (called PBPK models) rely on
the use of physiological information to ease development and validation.

The graph for the non-linear relationship between the various factors is represented by a curve;
the relationships between the factors can then be found by calculating the dimensions of
different areas under the curve. The models used in non-linear pharmacokinetics are largely
based on Michaelis–Menten kinetics. A reaction's factors of non-linearity include the following:

 Multiphasic absorption: Drugs injected intravenously are removed from the plasma through
two primary mechanisms: (1) Distribution to body tissues and (2) metabolism + excretion of
the drugs. The resulting decrease of the drug's plasma concentration follows a biphasic
pattern (see figure). Plasma drug concentration vs time
after an IV dose
o Alpha phase: An initial phase of rapid decrease in plasma concentration. The decrease
is primarily attributed to drug distribution from the central compartment (circulation) into
the peripheral compartments (body tissues). This phase ends when a pseudo-
equilibrium of drug concentration is established between the central and peripheral
compartments.
o Beta phase: A phase of gradual decrease in plasma concentration after the alpha
phase. The decrease is primarily attributed to drug elimination, that is, metabolism and
excretion.[10]
o Additional phases (gamma, delta, etc.) are sometimes seen.[11]
 A drug's characteristics make a clear distinction between tissues with high and low blood
flow.
 Enzymatic saturation: When the dose of a drug whose elimination depends on
biotransformation is increased above a certain threshold the enzymes responsible for its
metabolism become saturated. The drug's plasma concentration will then increase
disproportionately and its elimination will no longer be constant.
 Induction or enzymatic inhibition: Some drugs have the capacity to inhibit or stimulate their
own metabolism, in negative or positive feedback reactions. As occurs
with fluvoxamine, fluoxetine and phenytoin. As larger doses of these pharmaceuticals are
administered the plasma concentrations of the unmetabolized drug increases and
the elimination half-life increases. It is therefore necessary to adjust the dose or other
treatment parameters when a high dosage is required.
 The kidneys can also establish active elimination mechanisms for some drugs, independent
of plasma concentrations.
It can therefore be seen that non-linearity can occur because of reasons that affect the entire
pharmacokinetic sequence: absorption, distribution, metabolism and elimination.

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