DRUG METABOLISM

A drug may undergo a metabolic change at any stage after ingestion, both prior to reaching its site of action and afterwards. Much of drug metabolism takes place in the intestine and in the liver. The metabolic changes may lead to the deactivation and excretion of a compound before it has had any effect, bringing about the first pass loss. The metabolism of a drug may also change its activity and bring about side effects. In other instances the metabolite may actually be the active species. In these cases there is a pro-drug:drug relationship. As the drug passess through the system it is exposed to the digestive enzymes, which are often hydrolytic in their action. The bacterial action in the intestine is often reductive while the metabolism in the liver is often oxidative in character. It is possible to distinguish two phases in the metabolism of a drug. In phase one, changes are brought about to the drug itself. Alcohols and aldehydes may be oxidized, hydroxyl or epoxide groups may be inserted, alkyl groups may be removed from nitrogen or oxygen and polar functional groups such as amino and hydroxyl groups unmasked by the hydrolysis of amides and esters. In phase two, a polar molecule such as glycine 2.1, the sugar derivative, glucuronic acid 2.2, a sulfate group 2.3 or the tripeptide glutathione 2.4 is linked to the drug by a process known as ‘conjugation’. The overall effect of these changes is to increase the water solubility of the drug and to diminish its lipid solubility. This in turn can diminish the likelihood of it crossing various barriers and reaching its site of action. The addition of glutathione may remove a toxic metabolite.