The volume of distribution is the concentration of the drug in the body divided by the plasma concentration. Distribution is to three compartments: the vascular compartment (5% of body weight), the intracellular compartment (30% of body weight), and the extracellular compartment (15% of body weight). Molecular size, lipid solubility, and protein binding influence the volume of distribution. Highly lipophilic drugs easily traverse membranes and are easily distributed to all three compartments, whereas lipid-insoluble drugs do not easily cross tissue membranes and experience only a small volume of distribution. Large molecular size or highly protein-bound drugs rarely leave the vascular compartment and result in a limited volume of distribution.

After a drug enters the systemic circulation, it is distributed throughout the body. Distribution is generally uneven because of differences in regional blood flow related to "directed" cardiac output. Because of this, there are two phases of distribution within the body. In the first phase, the drug is distributed to the highly perfused vital organs (kidney, brain, and liver). In the next phase, drug is delivered to the lesser perfused organs (skin, fat, and muscle).

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