## Distribution

VOLUME OF DISTRIBUTION The volume of distribution (V) relates the amount of drug in the body to the concentration of drug (C) in the blood. This volume does not necessarily refer to an identifiable physiological volume but rather to the fluid volume that would be required to contain all the drug in the body at the same concentration measured in the blood:

Amount of drug in body / V = C, or V = amount of drug in body / C (1-6)

A drug's volume of distribution therefore reflects the extent to which it is present in extravas-cular tissues and not in the plasma. The plasma volume of a typical 70-kg man is 3 L, blood volume is about 5.5 L, extracellular fluid volume outside the plasma is 12 L, and the volume of total-body water is approximately 42 L.

Many drugs exhibit volumes of distribution far in excess of these values (see Appendix II in the 11th edition of the parent text). For drugs that are bound extensively to plasma proteins but that are not bound to tissue components, the volume of distribution will approach that of the plasma volume because drug bound to plasma protein is measurable. In contrast, certain drugs have high volumes of distribution even though the drug in the circulation is bound to albumin because these drugs are also sequestered elsewhere.

The volume of distribution may vary widely depending on the relative degrees of binding to high-affinity receptor sites, plasma and tissue proteins, the partition coefficient of the drug in fat, and accumulation in poorly perfused tissues. The volume of distribution for a given drug can differ according to patient's age, gender, body composition, and presence of disease. Total-body water of infants younger than 1 year of age, for example, is 75-80% of body weight, whereas that of adult males is 60%o and that of adult females is 55%.

The volume of distribution defined in Equation 1-6 considers the body as a single homogeneous compartment. In this one-compartment model, all drug administration occurs directly into the central compartment, and distribution of drug is instantaneous throughout the volume (V). Clearance of drug from this compartment occurs in a first-order fashion; i.e., the amount of drug eliminated per unit of time depends on the amount (concentration) of drug in the body compartment. Figure 1-3A and Equation 1-7 describe the decline of plasma concentration with time for a drug introduced into this central compartment:

where k is the rate constant for elimination that reflects the fraction of drug removed from the compartment per unit of time. This rate constant is inversely related to the t1/2 of the drug (k = 0.693/tm).

The idealized one-compartment model does not describe the entire time course of the plasma concentration. That is, certain tissue reservoirs can be distinguished from the central compartment, and the drug concentration appears to decay in a manner that can be described by multiple exponential terms (Figure 1-3B). Nevertheless, the one-compartment model is sufficient to apply to most clinical situations for most drugs and the drug t1/2 in the central compartment dictates the dosing interval for the drug.