Volume of Distribution

VOLUME OF DISTRIBUTION

A drug in circulation distributes to various organs and tissues. When the process of distribution is complete (at distribution equilibrium), different organs and tissues contain varying concentrations of drug which can be determined by the volume of tissues in which the drug is present. Since different tissues have different concentrations of drug, the volume of distribution cannot have a true physiologic meaning. However, there exists a constant relationship between the concentration of drug in plasma, C, and the amount of drug in the body, X.

V  ∝ C

or, X = V_dC                       (3.4)

where V_d = proportionality constant having the unit of volume and popularly called as apparent volume of distribution. It is defined as the hypothetical volume of body fluid into which a drug is dissolved or distributed. It is called as apparent volume because all parts of the body equilibrated with the drug do not have equal concentration.

Thus, from equation 3.4, V_d is given by the ratio:

Apparent Volume of Distribution = Amount of drug in the body / Plasma drug concentration

or,

V_d = X/C              (3.5)

The apparent volume of distribution bears no direct relationship with the real volume of distribution.

The real volume of distribution has direct physiologic meaning and is related to the body water. The body water is made up of 3 distinct compartments as shown in the Table 3.4.

TABLE 3.4.

Fluid Compartments of a 70 Kg Adult

The volume of each of these real physiologic compartments can be determined by use of specific tracers or markers (Table 3.5). The plasma volume can be determined by use of substances of high molecular weight or substances that are totally bound to plasma albumin, for e.g. high molecular weight dyes such as Evans blue, indocyanine green and I-131 albumin. When given i.v., these remain confined to the plasma. The total blood volume can also be determined if the haematocrit is known. The extracellular fluid (ECF) volume can be determined by substances that easily penetrates the capillary membrane and rapidly distribute throughout the ECF but do not cross the cell membranes, for e.g. the Na⁺, Cl ^-, Br^–, SCN^– and SO₄^2– ions and inulin, mannitol and raffinose. However, none of these substances are completely kept out of the cells. The ECF volume, excluding plasma is approximately 15 litres. The total body water (TBW) volume can be determined by use of substances that distribute equally in all water compartments of the body (both intra- and extracellular), for e.g. heavy water (D₂O), tritiated water (HTO) and lipid soluble substances such as antipyrine. The intracellular fluid volume is determined as the difference between the TBW and ECF volume. The intracellular fluid volume including those of blood cells is approximately 27 litres.

TABLE 3.5.

Markers Used to Measure the Volume of Real Physiological Compartments

Since the tracers are not bound or negligibly bound to plasma or tissue proteins, their apparent volume of distribution is same as their true volume of distribution. The situation is different with most drugs which bind to plasma proteins or extravascular tissues or both. Certain generalizations can be made regarding the apparent volume of distribution of such drugs:

1. Drugs which bind selectively to plasma proteins or other blood components, e.g. warfarin (i.e. those that are less bound to extravascular tissues), have apparent volume of distribution smaller than their true volume of distribution. The V_d of such drugs lies between blood volume and TBW volume (i.e. between 6 to 42 litres); for example, warfarin has a V_d of about 10 litres.

2. Drugs which bind selectively to extravascular tissues, e.g. chloroquine (i.e. those that are less bound to blood components), have apparent volume of distribution larger than their real volume of distribution. The V_d of such drugs is always greater than 42 litres or TBW volume; for example, chloroquine has a V_d of approximately 15,000 litres. Such drugs leave the body slowly and are generally more toxic than drugs that do not distribute deeply into body tissues.

Thus, factors that produce an alteration in binding of drug to blood components, result in an increase in V_d and those that influence drug binding to extravascular components result in a decrease in V_d. Other factors that may influence V_d are changes in tissue perfusion and permeability, changes in the physicochemical characteristics of the drug e.g. ionisation, changes in the body weight and age and several disease states.

Apparent volume of distribution is expressed in litres and sometimes in litres/Kg body weight. The V_d of various drugs ranges from as low as 3 litres (plasma volume) to as high as 40,000 litres (much above the total body size). Many drugs have V_d greater than 30 litres. The V_d is a characteristic of each drug under normal conditions and is altered under conditions that affect distribution pattern of the drug.