Two-compartment open model:
Definition:
The two-compartment open model is a pharmacokinetic compartment model which
considers that the body has two compartments – the central compartment and the peripheral
compartment and the drug in these compartments is in equilibrium with each other.
Assumptions:
1. The central compartment is composed of blood, extracellular fluid and highly perfused
tissues (e.g. kidney, liver etc.) in which the drug distributes itself rapidly and uniformly.
2. The peripheral compartment consists of tissues to which the drug equilibrates more
slowly.
3. The transfer of drug between the two compartments occurs via 1 st-order process.
4. The elimination of drug occurs from the central compartment unless specifically known
to be otherwise for a drug.
Diagram and description:
There are three types of two compartment models to be considered –
IV ka
Central compartment k12 Tissue compartment
Central compartment k12 Tissue compartment
Dp Vp Cp Dp Vp Cp k21 Dt Vt Ct
k21 Dt Vt Ct
Model A
k k
IV administration Extravascular administration
IV ka
Central compartment k12 Tissue compartment
Central compartment k12 Tissue compartment
Dp Vp Cp k21 Dt Vt Ct
Dp Vp Cp k21 Dt Vt Ct
Model B
k
k
IV administration Extravascular administration
IV ka
Central compartment k12 Tissue compartment
Central compartment k12 Tissue compartment Dp Vp Cp k21 Dt Vt Ct
Dp Vp Cp k21 Dt Vt Ct
k k
Model C
k k
IV administration Extravascular administration
Among the above models, model A is most widely used because the central compartment is most
well connected to eliminatory organs.
The two-compartment model came to being because many drugs bi-exponential decline in plasma
concentration. If the drug had followed one-compartment model then plasma concentration decline
would be mono-exponential (i.e. only due to elimination).
In the two-compartment model, it is considered that the drug first enters the central compartment
and is immediately distributed in the compartment homogeneously. This gives us the initial plasma
concentration. Then the drug slowly distributes into the peripheral compartment from the central
compartment following 1st-order kinetics.
As a result, the amount of drug in central compartment is decreased and hence the drug
concentration in that compartment also decreases. Hence plasma concentration declines. This is
called the distribution phase. Then the drug is eliminated from the central compartment. This again
causes decline of plasma drug concentration. This is called the elimination phase.
Determination of apparent volume of distribution of drugs following two-compartment model:
In case of one-compartment open model, the determination of apparent volume of distribution is
straight-forward – we measure the initial plasma concentration and then divide the amount of drug
in body (in case of IV bolus, it would be equal to the amount of drug administered) by the measured
conc.
But in case of two-compartment model, this is not so straight-forward because the drug is
distributed in two different compartments at two different concentrations. So we can’t use the
plasma drug conc. as the representative of drug conc. in the body. We can only determine the
volume of distribution at steady-state when the distribution is complete.
Now, let’s consider that the volume of distribution of the drug in central compartment is Vp. The
concentration of the drug in this compartment is given by the plasma conc. Cp. So, the amount of
drug in central compartment is –
D p VpC p
Similarly, the amount of drug in tissue is given by –
D t Vt C t
Vt Ct
Here, is the apparent volume of distribution in peripheral compartment, is the
concentration of the drug in peripheral compartment. Now, the total drug in the body ( D B ) is
given by –
D B D p D t ..................(2)
At steady state, the rates of drug transfer between the two compartments are equal. So –
D t k 21 D p k 12
k 12
Dt Dp
k 21
k 12
Dt Vp C p
k 21
Now, the steady-state volume of distribution –
DB
VDSS
Cp 4 Mark must asbe exam e
D p Dt
VDSS
Cp
k12
V pC p V pC p
k 21
VDSS
Cp
k12
VDSS V p Vp
k 21
Here, k 12 , k 21 etc. are termed micro-constants. Their values can’t be estimated directly.
Application:
Two-compartment models are important for drugs which are highly distributed and have
special distribution to peripheral tissue. e.g. Isotretinoin.
Three-compartment models:
Definition:
Three-compartment model is a pharmacokinetic model which considers that the body has
three compartments – a central compartment, a peripheral compartment of shallow tissue and
another peripheral compartment of deep tissue.
Types:
There are two types of three-compartment models –
1. Mamillary model
2. Catenary model (described above)
Diagram of mamillary three-compartment model:
IV
k21 Central compartment k13 Deep tissue compartment
Tissue compartment
Vt Ct Dt k12 Vp Cp Dp k31 Vdt Cdt Ddt
k
Figure: Three-compartment model for IV administration
ka
k21 Central compartment k13 Deep tissue compartment
Tissue compartment
Vt Ct Dt k12 Vp Cp Dp k31 Vdt Cdt Ddt
k
Figure: Three-compartment model for Extravascular administration
According to this model, the drug is first distributed in the central compartment. This
process is very rapid. Then the drug distributes to the peripheral compartments from the central
compartment. The distribution into deep tissues is slower than that into shallow tissues
(compartment 2). All distribution occurs via 1st-order processes.
Application:
Three-compartment model is not widely used. Its use mainly lies for those drugs which are
distributed to deep tissues such as bone and bone marrow, deep fat etc.
Important examples include antibacterial specially the anti-tubercular drugs. The pathogens
responsible for tuberculosis may reside in the bone marrow and remain latent and even infect the
next generation. Thus, the pathogens must be destroyed from the bone marrow as well.
This model is useful for Isoniazid, Ethambutol, Pyrazinamide and Rifampin.