1.5 Metabolism
Metabolism
After a drug has been absorbed and distributed throughout the body, it is broken down by a process known as metabolism so that it can be excreted from the body. Drugs undergo chemical alteration by various body systems to create compounds that are more easily excreted.
As previously discussed in this chapter, medications that are swallowed or otherwise administered into the gastrointestinal tract are inactivated by the intestines and liver, known as the first-pass effect. Additionally, everything that enters the bloodstream, whether swallowed, injected, inhaled, absorbed through the skin, or produced by the body itself, is metabolized by the liver. See Figure 1.5[1] for an image of the liver. These chemical alterations are known as biotransformations. The biotransformations that take place in the liver are performed by liver enzymes.
Biotransformations occur by mechanisms categorized as either Phase I (modification), Phase II (conjugation), and in some instances, Phase III (additional modification and excretion.)[2]
Phase I biotransformations alter the chemical structure of the drug. Many of the products of enzymatic breakdown, called metabolites, are less chemically active than the original molecule. For this reason, the liver is referred to as a “detoxifying” organ. An example of a Phase I biotransformation is when diazepam, a medication prescribed for anxiety, is transformed into desmethyldiazepam and then to oxazepam. Both these metabolites produce similar physiological and psychological effects of diazepam.[3]
In some instances, Phase I biotransformations change an inactive drug into an active form called a “prodrug.” Prodrugs improve a medication’s effectiveness. They may also be designed to avoid certain side effects or toxicities. For example, sulfasalazine is a medication prescribed for rheumatoid arthritis. It is prodrug that is not active in its ingested form but becomes active after Phase I modification.
Phase II biotransformations involve reactions that couple the drug molecule with another molecule in a process called conjugation. Conjugation typically renders the compound pharmacologically inert and water-soluble so it can be easily excreted. These processes can occur in the liver, kidney, lungs, intestines, and other organ systems. An example of Phase II metabolism is when oxazepam, the active metabolite of diazepam, is conjugated with a molecule called glucuronide so that it becomes physiologically inactive and is excreted without further chemical modification.[4]
Following Phase II metabolism, Phase III biotransformations may also occur, where the conjugates and metabolites are excreted from cells.[5]
Factors Affecting Metabolism
Critical factors in drug metabolism are the type and concentration of liver enzymes. The most important enzymes for medical purposes are monoamine oxidase and cytochrome P450. These two enzymes are responsible for metabolizing dozens of chemicals.[6]
Drug metabolism can be infl