Skip to Main Content

CHAPTER OBJECTIVES

  • Describe the pathways for drug elimination in the body.

  • Describe the role of hepatic blood flow and drug protein binding on hepatic elimination.

  • Describe the biotransformation of drugs in the liver and which enzymatic processes are considered “phase I reactions” and “phase II reactions.”

  • List the organs involved in drug elimination and the significance of each.

  • Discuss the relationship between metabolic pathways and enzyme polymorphisms on inter-subject variability and drug–drug interactions.

  • Describe how the exposure of a drug is changed when coadministered with another drug that shares the same metabolic pathway.

  • Define first-pass metabolism.

  • Use urine data to calculate fraction of drug excreted and metabolized.

  • Describe biliary drug excretion and define enterohepatic drug elimination.

  • Discuss the reasons why bioavailability is variable and can be less than 100%.

  • Describe BDDCS—Biological Drug Disposition Classification System.

  • Describe the processes for renal drug excretion and explain which renal excretion process predominates in the kidney for a specific drug.

INTRODUCTION

The decline from peak plasma concentrations after drug administration results from drug elimination or removal by the body. The elimination of most drugs from the body involves the processes of both metabolism (biotransformation) and renal excretion. The liver and kidney are the two major drug eliminating organs in the body, though drug elimination can also occur almost anywhere in the body. For many drugs, the principal site of metabolism is the liver. However, other tissues or organs, especially those tissues associated with portals of drug entry into the body, may also be involved in drug metabolism. These sites include the lung, skin, gastrointestinal mucosal cells, microbiological flora in the distal portion of the ileum, and large intestine. The kidney may also be involved in certain drug metabolism reactions.

In this chapter, we will see how drugs are eliminated from the body. Non-endogenous drugs are viewed as foreign substances (xenobiotics) by the body, which will then be eliminated as efficiently as possible. In a simplifying scheme, hydrosoluble drugs can be readily excreted from the body by the kidney, while liposoluble drugs are generally transformed by the liver into either relatively small molecular weight metabolites that are more water soluble and can then be excreted by the kidney, or into larger MW metabolites such as conjugates that will then be excreted via the bile and eventually in the feces. We will provide a review of the liver and of its importance in the metabolism of drugs. We will then also discuss biliary excretion, and finally renal elimination.

ANATOMY AND PHYSIOLOGY OF THE LIVER

The liver is the major organ responsible for drug metabolism and where enzymes are of utmost importance in transforming drugs. However, intestinal tissues, lungs, kidney, and skin also contain appreciable amounts of biotransformation enzymes, as reflected by human data (Table 6-1a). Metabolism may also occur in other tissues to a lesser degree depending ...

Pop-up div Successfully Displayed

This div only appears when the trigger link is hovered over. Otherwise it is hidden from view.