Multicompartment Models (Delayed Distribution Models)

MULTICOMPARTMENT MODELS

(Delayed Distribution Models)

One-compartment model adequately describes pharmacokinetics of many drugs. Instantaneous distribution equilibrium is assumed in such cases and decline in the amount of drug in the body with time is expressed by an equation with a monoexponential term (i.e. elimination). However, instantaneous distribution is not truly possible for an even larger number of drugs and drug disposition is not monoexponential but bi- or multi-exponential. This is because the body is composed of a heterogeneous group of tissues each with different degree of blood flow and affinity for drug and therefore different rates of equilibration. Ideally, a true pharmacokinetic model should be the one with a rate constant for each tissue undergoing equilibrium, which is difficult mathematically. Multicompartment models are thus based on following assumptions –

1. Blood/plasma and the highly perfused tissues such as tissues such as brain, heart, lung, liver and kidneys constitute the central compartment.

2. Other tissues with similar distribution characteristics are pooled together to constitute peripheral compartments tissues on the basis of similarity in their distribution characteristics.

3. Intravenously administered medications are introduced directly into the central compartment.

4. Irreversible drug elimination, either by hepatic biotransformation or renal excretion, takes place only from the central compartment.

5. Reversible distribution occurs between central and peripheral compartments, with a finite time required for distribution equilibrium to be attained.

6. After drug equilibration between drug and the peripheral compartments, elimination of drug follows first-order kinetics.

7. All rate processes involving passage of drug in and out of individual compartment are first-order processes and plasma level-time curve is best described by sum of series of exponential terms each corresponding to first-order rate processes associated with a given compartment.

8. The peripheral compartment is usually inaccessible to direct measurement and is not a site of drug elimination or clearance

Multicompartment characteristics of a drug are best understood by giving it as i.v. bolus and observing the manner in which the plasma concentration declines with time. The number of exponentials required to describe such a plasma level-time profile determines the number of kinetically homogeneous compartments into which a drug will distribute.