clinical pharmacology
Drug Distribution to Tissues
Binding
The extent of drug distribution into tissues depends on the degree of plasma protein and tissue binding. In the bloodstream, drugs are transported partly in solution as free (unbound) drug and partly reversibly bound to blood components (eg, plasma proteins, blood cells). Of the many plasma proteins that can interact with drugs, the most important arealbumin, alpha-1 acid glycoprotein, and lipoproteins. Acidic drugs are usually bound more extensively toalbumin; basic drugs are usually bound more extensively to alpha-1 acid glycoprotein, lipoproteins, or both. Only unbound drug is available for passive diffusion to extravascular or tissue sites where the pharmacologic effects of the drug occur. Therefore, the unbound drug concentration in systemic circulation typically determines drug concentration at the active site and thus efficacy. At high drug concentrations, the amount of bound drug approaches an upper limit determined by the number of available binding sites. Saturation of binding sites is the basis of displacement interactions among drugs (see Binding ). Drugs bind to many substances other than proteins. Binding usually occurs when a drug associates with a macromolecule in an aqueous environment but may occur when a drug is partitioned into body fat. Because fat is poorly perfused, equilibration time is long, especially if the drug is highly lipophilic. Accumulation of drugs in tissues or body compartments can prolong drug action because the tissues release the accumulated drug as plasma drug concentration decreases. For example, thiopental is highly lipid soluble, rapidly enters the brain after a single IV injection, and has a marked and rapid anesthetic effect; the effect ends within a few minutes as the drug is redistributed to more slowly perfused fatty tissues. Thiopental is then slowly released from fat storage, maintaining subanesthetic plasma levels. These levels may become significant if doses of thiopental are repeated, causing large amounts to be stored in fat. Thus, storage in fat initially shortens the drug’s effect but then prolongs it. Some drugs accumulate within cells because they bind with proteins, phospholipids, or nucleic acids. For example,chloroquineconcentrations in white blood cells and liver cells can be thousands of times higher than those in plasma. Drug in cells is in equilibrium with drug in plasma and moves into plasma as the drug is eliminated from the body. 