02.03.1 Introduction

As we discussed previously (Section 2.2), absorption from the gastrointestinal tract is best for lipid soluble drugs. Lipid soluble drugs are also readily reabsorbed from the kidney tubule. Thus, lipid soluble drugs are difficult to get rid of, as even when they get into the kidney tubule, they are reabsorbed rather than excreted. Water soluble compounds are readily excreted from the kidney. Thus, for excretion of a drug, it is necessary to turn a lipid soluble drug into a water soluble (hydrophilic) drug, which can then be excreted in the urine. This change from a lipid soluble to a water soluble compound involves metabolism, which usually has two phases, Phase I and II metabolism. In addition to increasing water solubility, metabolism usually produces metabolites that are inactive, and thus reduces the activity of the drug.

Our enzyme systems are not designed to metabolise drugs. However, the normal physiological enzyme pathways for metabolism of endogenous compounds (substances found in the body) are used in drug metabolism. The body also has systems for metabolising xenobiotics (substances foreign to the body), as part of the body’s defence system. These xenobiotic metabolising enzymes are also used in drug metabolism.

The liver is the main site of metabolism. Because of this, drug metabolism is changed in hepatic insufficiency. However, the liver is not the only site of drug metabolism. In addition to the liver, metabolising enzymes are present in high concentrations in the intestine, nasal mucosa and lung, and these tissues are all capable of metabolising certain drugs. Most of the discussion of metabolism in this chapter is of liver metabolism.