02.02.3 Factors that Modify Protein Binding and Drug Distribution?

A decrease in blood proteins leads to an increase in free drug concentration and effects, and the effects may go from therapeutic to toxic. Blood proteins are decreased by dietary protein insufficiency (malnutrition), liver disease causing decreased synthesis of proteins, and by burns. When there are decreased plasma proteins, it may be necessary to decrease the dose of drug, to decrease the free concentration of a drug, to go from a toxic effect to a therapeutic effect.

Conversely, when there is an increase in blood proteins, there may be a decrease in the free drug concentration and the effect of the drug may be lost, as the free plasma concentration goes below that needed for a therapeutic effect. For instance, in multiple myeloma, there is excessive production of immunoglobulin proteins, which bind and inactivate certain drugs. Thus, in multiple myeloma, it may be necessary to increase the dose of a drug to increase the free concentration, and get a therapeutic effect.

The lipid solubility of a drug is an important factor determining distribution. Lipophilic drugs are accumulated in fat tissue, and are only slowly released from fat tissue. For instance, the anti-arrhythmic drug amiodarone is very lipophilic, and is accumulated to a great extent in lipids. When the administration of amiodarone is stopped, amiodarone continues to be released out of the fat tissues for weeks. Amiodarone can be a toxic drug. Unfortunately, the toxic effects of amiodarone are slow to reverse, as reversal requires the removal of amiodarone, and that may take weeks.

Another example of a highly lipophilic drug is marijuana. After a single use of marijuana, marijuana accumulates in the fat and is slowly released. As a result of this, marijuana can be detected in blood 6 weeks after a single use.