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  • Explain the importance of drug distribution in determining drug effect.

  • Identify barriers to the distribution of drugs into tissues.

  • Describe the dynamic of drug binding to constituents in blood and the impact on drug distribution in the body.

  • Provide a concise statement of the free drug hypothesis.

  • Describe the effects of membrane transporters on drug distribution into select tissues, such as the brain.

  • Differentiate between the various methods to quantify the distribution of drugs in the body.

  • Predict the effects of changes in protein binding on drug distribution.

  • Describe the factors that alter the protein binding of drugs to albumin and α1-acid glycoprotein.

  • Describe the primary methods to determine plasma and serum protein binding of drugs.

  • Determine drug binding constants from in vitro data.

  • Predict the probable clinical impact of protein binding displacement interactions.


Drugs are rarely administered or applied directly to their site of action. Even topical application commonly targets sites under or within, rather than on the skin. Hence, after a drug passes barriers to gain entry into the body, it must move from the entry site to the anatomical location(s) where the pharmacologic effect will occur. Unlike a guided missile, drug molecules do not home in on their desired site of action (though scientists are working to develop such drug products). Rather, they are subject to dynamic forces within the body similar to those that govern the movement of endogenous substances such as electrolytes and hormones. The extent and speed of this movement through the body—referred to as distribution—plays a critical role in drug effect.

Consider the case of anesthetic drugs. Patients receiving such drugs move through two stages prior to entering a level of central nervous system (CNS) depression known as surgical anesthesia (Wilson, 1981). The first stage (known simply as Stage I) produces analgesia. In Stage II, patients exhibit excitement and may vocalize delirium (though they will not remember this since the anesthetic produces amnesia). A patient’s respiration, heart rate, and blood pressure increase during this stage. Stage III is the desired state—surgical anesthesia. Obviously, it is best to move through Stage II and into Stage III as rapidly as possible. The speed at which an anesthetic moves from the blood into the brain is the key determinant of the speed of progression through these stages and into surgical anesthesia. Thus, the best anesthetic agents for induction of anesthesia are those which rapidly distribute into the brain.

This example illustrates the importance of understanding drug distribution for the rational use of drugs. This chapter reviews the basic concepts of drug distribution, describes how drug distribution in the body can be measured, and discusses the effects of one of the most important factors influencing drug distribution—protein binding.


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