Pharmacokinetics: Comapartment Modelling

COMPARTMENTAL MODELS

·         Here the body can be represented as series, or systems, of compartments that communicate reversibly with each other. A compartment is not a real physiologic or anatomic region but is considered as a tissue or group of tissues that have similar blood flow and drug affinity. Within each compartment, the drug is considered to be uniformly distributed.

·         Rate constants are used to represent the overall rate processes of drug entry into and exit from the compartment. The model is an open system since the drug can be eliminated from the system.

·         Depending upon whether the compartments are arranged parallel or in a series, compartmental models are divided in two categories-

§  Mammillary model

§  Caternary model.

 MAMMILLARY MODEL:

This model is the most common compartmental used in pharmacokinetics. It consists of one or more peripheral compartments connected to the central compartment in a manner similar to connection of satellites to a planet (i.e., joined parallel to the central compartment).

Central compartment (or compartment-1):-

• It comprises of plasma and highly perfused tissues such as lungs, liver, kidneys, etc. which rapidly equilibrates with drug.
• The drug is directly absorbed into this compartment.
• Elimination too occurs from this compartment since the chief organs involved in drug elimination are liver and kidneys, the highly perfused tissues and therefore presumed to be rapidly accessible to drug in the systemic circulation.

Peripheral compartments or tissue compartment (compartment 2, 3, etc.):-

• Those are with low vascularity and poor perfusion.
• Distribution of drugs to these compartments is through blood.
• Movement of drug between compartments is defined by characteristic first order rate constant denoted by “K”.
• K₁₂→Drug movement from compartment 1 to compartment 2
• K₂₁→Reverse.
• Number of rate constants which will appear in a particular compartment model is given by R.
• For intravenous → R=2n-1
• For extravenous →R= 2n

Where n= number of compartments.

Model 1

One compartment open model, intravenous administration

Model 2

One compartment open model, extravascular administration (oral, rectal, etc.)

Model 3

Two compartment open model, intravenous administration.

Model 4

Two compartment open model, extravascular administration

Model 5

Three compartment open model, intravenous administration

Model 6

Three compartment open model, extravascular administration.

Figure: Various mammillary compartment models. The rate constant K₀₁ is basically K_a, the first order absorption rate constant and K₁₀ is K_E the first order elimination rate constant.

CATERNARY MODEL:

                In this model, the compartments are joined to one another in a series, like compartments of a train. This is not observable physiologically and anatomically as the various organs are directly linked to the blood compartment. Hence this model is rarely used.

Figure. A Caternary model

ADVANTAGES OF COMPARTMENT MODELING:

Ø  It gives visual representation of various rate processes involved in drug disposition.

Ø  It shows how many rate constants are necessary to describe these processes.

Ø  It enables to write differential equations for each of the rate processes in order to describe drug concentration changes in each compartment.

Ø  It is useful in predicting drug concentration-time profile in both normal physiologic and in pathologic conditions.

Ø  It is important in the development of dosage regimens.

DISADVANTAGES OF COMPARTMENT MODEL:

Ø  The compartments and parameters bear no relationship with the physiologic functions or the anatomic structure of the species.

Ø  Extensive efforts are required in the development of an exact model that predicts and describes correctly the ADME of a certain drug.

Ø  The model is based on curve fitting of plasma concentration with complex multiexponential mathematical equations.

Ø  The model may vary within a study population.

Ø  The approach can be applied only to a specific drug under study.

Ø  A drug given by IV route may behave according to single compartment  model but the same drug given by oral route may show two compartmental behavior, thus the type of compartment model may change with route of administration.

Difficulties generally arise when using model to interpret the differences between results from human and animal experiments.