Following the absorption into the systemic circulation, drugs are distributed both into the extracellular and intracellular milieu. However, the determinants that affect a drug’s diffusion across biological membranes and the drug’s plasma protein binding limit its ability to leave the vascular compartment. Even so, lipid soluble drugs will reach their receptors in highly perfused organs such as the heart, liver, kidney, and brain within minutes of absorption.

Since only the free form of a drug is capable of diffusion, plasma protein binding reduces a drug’s availability to cross biological membranes. Albumin is the most abundant protein in plasma and it is responsible for most plasma protein binding of drugs. Highly protein bound drug tends to remain in the vascular compartment and have a low volume of distribution (Vd). Plasma protein binding is also an important mechanism for drug-drug interactions.

The Vd represents the fluid volume that would be required to contain the total amount of absorbed drug in the body at a uniform concentration equivalent to that in plasma at steady state, i.e., Vd = Dose / [Drug]plasma. Thus, for two drugs of equal potency, the drug that is more highly distributed among body tissues will generally require a higher initial dose to establish a therapeutic plasma concentration than the drug that is less highly distributed.

The distribution of drugs to the central nervous system (CNS) and cerebral spinal fluid is restricted by the blood-brain barrier. However, the only limiting factor associated with highly lipid-soluble drugs is cerebral blood flow. Redistribution may affect the duration of a drug effect, for example, when a drug of high lipid solubility, which first acts on the brain or cardiovascular system after administration is redistributed to other tissues.