The volume of distribution is an apparent fluid volume required to contain the entire drug within various body compartments at the same concentration as in the plasma. The intracellular fluid compartment constitutes two-thirds of total body water, whereas the extracellular fluid compartment—comprising plasma and interstitial fluid—accounts for one-third. High-molecular-weight or plasma-protein-bound drugs cannot pass through capillary slit junctions and accumulate in the plasma. Such drugs exhibit low Vd. Low-molecular-weight hydrophilic drugs can cross slit junctions but cannot penetrate the cell's lipid membranes, so they accumulate in the extracellular space. Low-molecular-weight lipophilic drugs can cross slit junctions and also easily enter intracellular space. Such drugs have high Vd. Since such drugs remain in extraplasmic space longer, they are not accessible to the organs of elimination. So, they stay in the body with prolonged action. Due to their tendency to escape from plasma, they have a high Vd, and a higher loading dose is necessary to achieve the desired plasma concentration. Similarly, since drugs with a low Vd remain longer in the plasma, a lower dose is required.