The volume of distribution refers to the theoretical volume necessary to contain the entire amount of an administered drug at the same concentration observed in the blood plasma. The body's intracellular fluid compartment, which makes up two-thirds of the total body water, is contrasted with the extracellular fluid compartment—comprising plasma and interstitial fluid—that accounts for one-third. The volume of distribution can vary depending on the characteristics of the drug. High-molecular-weight or plasma-protein-bound drugs, which cannot pass through capillary slit junctions, accumulate in the plasma and have a low volume of distribution. Conversely, low-molecular-weight hydrophilic drugs can cross slit junctions but cannot penetrate the cell's lipid membranes, leading to accumulation in the extracellular space. Low-molecular-weight lipophilic drugs, which can cross slit junctions and easily enter the intracellular space, have a high volume of distribution. These drugs stay in the body longer because they remain in the extraplasmic space, making them inaccessible to elimination organs. This also means they require a higher loading dose to achieve the desired plasma concentration. In contrast, drugs with a low volume of distribution stay longer in the plasma, requiring a lower dose.
