Weak acids and bases are not readily eliminated from the body. Metabolism fosters drug clearance by biotransformation into more polar, i.e., more water-soluble fractions. The main site of drug metabolism is the liver. The lungs, skin, kidneys, gastrointestinal mucosa, and plasma enzymes may play minor roles. Metabolism or biotransformation is also responsible for converting some drugs (pro-drugs), which are inactive, into their active metabolites.

The chemical reactions associated with metabolism or biotransformation of drugs is classified into two types: Phase I or Phase II reactions. Phase I reactions are mediated by the hepatic microsomal CYP450 enzyme system and involve metabolic modification of a drug by oxidation or reduction. This system can be “induced” to increase or reduce the rate of a drug’s metabolism and is responsible for many drug-drug interactions.

There is much genetic variability (polymorphism) with the CYP450 enzyme system. For example, the demethylation of codeine (a pro-drug) by the CYP450 isoenzyme 2D6 is subject to genetic polymorphism. Up to 10% of the general population metabolize codeine poorly and do not experience analgesia in response to treatment with codeine, while another 10% rapidly convert codeine to morphine and experience potentially severe toxicity (including death).

In Phase II reactions drugs are either hydrolyzed or conjugated to endogenous macromolecules (e.g., glucuronic acid, sulphate, glycine, glutamine, or acetate) in order to facilitate the drugs’ clearance. The terminology Phase I and Phase II does not imply a hierarchy in sequential steps. For example, acetaminophen, which is primarily metabolized by Phase II reactions, with higher doses may undergo Phase I and then another Phase II reaction (Figure 9).

Figure 9.
metabolism of acetaminophen
The metabolism of acetaminophen.