Even more problematic ideas of distribution.....

The simplest idea of the volume of distribution (Vd) of a drug, is to think of it as the volume that a drug distributes into when that drug is administered into the body, but before any elimination has taken place. The simplest approach therefore is to divide the dose of the drug (intravenously administered) by the observed plasma concentration at zero time, C0, i.e. before any elimination has had a chance to occur.

Vd = Dose/C0

Not all of any drug, however, is uniformly distributed throughout the body; and what is seen in the plasma only represents a fraction of all of the drug molecules distributed throughout the body. If more is distributed outside of the plasma 'compartment', the C0 will be smaller for a given dose of drug, and the Vd will appear correspondingly higher. The converse is also true, that if less is distributed outside of the plasma compartment, the Vd will appear lower.

The original ideas of the process of distribution, was that drug molecules were mostly freely permeable entities, and found a 'distributional equilibrium' across cell and tissue membranes. Binding to proteins or other large molecules prevented their effective permeation across membranes, and therefore 'trapped' these drug molecules into various 'compartments'.

Conceptually therefore, the Vd of a drug may be seen to be 'governed' by an expression relating body volumes (presumably determined by body weight), plasma protein binding and tissue binding:

Vd = Volume of central compartment + Volume of peripheral tissue x (fu/fut),

where central compartment referred to plasma volume, tissue referred to undefined number of tissues outside of plasma, fu is unbound or free fraction of drug in plasma, and fut is the unbound fraction of drug in the tissues.

By this expression one can see that the Vd can be reasonably expected to be related directly to the extent of tissue binding, and inversely related to the extent of plasma protein binding.

The Vd of a drug can also be seen to have direct and immediate effects on the starting concentrations of any drug administered, particularly if administered intravenously. And if the starting concentrations were responsible for efficacy or toxicity, the Vd may be expected to be a major determinant of efficacy or toxicity.

Knowing the Vd also helps us estimate the starting dose of a drug if we have a target drug concentration in mind. For this reason, dosage regiments of drugs with large Vds often incorporate a loading dose regiment before settling into a lower maintenance dose regiment.