Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and the tissues. For drugs administered IV, absorption is not a factor, and the initial phase (from immediately after administration through the rapid fall in concentration) represents the distribution phase, during which the drug rapidly leaves the circulation and enters the tissues.
The distribution of a drug from the plasma to the interstitium depends on cardiac output and local blood flow, capillary permeability, the tissue volume, the degree of binding of the drug to plasma and tissue proteins, and the relative lipophilicity of the drug
The rate of blood flow to the tissue capillaries varies widely. For instance, blood flow to the “vessel-rich organs” (brain, liver, and kidney) is greater than that to the skeletal muscles. Adipose tissue, skin, and viscera have still lower rates of blood flow. Variation in blood flow partly explains the short duration of hypnosis produced by an IV bolus of propofol. High blood flow, together with high lipophilicity of propofol, permits rapid distribution into the CNS and produces anesthesia
Capillary permeability is determined by capillary structure and by the chemical nature of the drug. Capillary structure varies in terms of the fraction of the basement membrane exposed by slit junctions between endothelial cells. In the liver and spleen, a significant portion of the basement membrane is exposed due to large, discontinuous capillaries through which large plasma proteins can pass. In the brain, the capillary structure is continuous, and there are no slit junctions. To enter the brain, drugs must pass through the endothelial cells of the CNS capillaries or be actively transported.
Binding of drugs to plasma proteins and tissues
Reversible binding to plasma proteins sequesters drugs in a non-diffusible form and slows their transfer out of the vascular compartment. Albumin is the major drug-binding protein and may act as a drug reservoir.
Many drugs accumulate in tissues, leading to higher concentrations in tissues than in the extracellular fluid and blood. Drugs may accumulate as a result of binding to lipids, proteins, or nucleic acids. Drugs may also be actively transported into tissues. Tissue reservoirs may serve as a major source of the drug and prolong its actions or cause local drug toxicity. (For example, acrolein, the metabolite of cyclophosphamide, can cause hemorrhagic cystitis because it accumulates in the bladder.)
The chemical nature of a drug strongly influences its ability to cross cell membranes. Lipophilic drugs readily move across most biologic membranes. These drugs dissolve in the lipid membranes and penetrate the entire cell surface. The major factor influencing the distribution of lipophilic drugs is blood flow to the area. In contrast, hydrophilic drugs do not readily penetrate cell membranes and must pass through slit junctions.