Medical Pharmacology Topics
Organs that contain biotransformation enzymes in order of importance are: liver, kidney, and others. Metabolic reaction are either synthetic (Phase II) or non-synthetic (Phase I). All synthetic metabolic reactions are conjugations. Non-synthetic reactions may be oxidations, reductions or hydrolysis. Phase I reactions usually occur before Phase II reactions. Some drugs skip Phase I and undergo conjugation directly.
A given drug will have several biotransformation pathways, depending on genetic variation. The reactions a drug will undergo are determined by its functional groups.
There is a limited number of Phase II reactions and they are relatively predictable. Drugs may be conjugated to glucoronic acid, amino acids, acetic acid, sulfate or a methyl group. There is a wide variety of non-synthetic reactions, and they are hard to predict.
When a drug is administered, concentration changes occur not only of the drug but its metabolites. These metabolites may be inactive, have the same or similar activity as the parent drug, or have a completely different activity. A pro drug is a therapeutic agent that does not have an activity by itself but is activated after converted to a metabolite. Most Phase I reactions yield inactive metabolites, although activation may occur with some agents. Phase II reactions almost always inactivate drugs, except for methylation. Phase II metabolites are almost always less lipophilic, while Phase I metabolites are usually less lipophilic than the parent drug.
Drug metabolizing enzymes are classified as either microsomal or non-microsomal. Microsomal enzymes are located in the endoplasmic reticulum and their substrates must be lipid-soluble. Most foreign and a few endogenous compounds are metabolized by microsomal enzymes. Virtually all oxidations, reductions and hydrolysis, as well as glucoronide conjugations are catalyzed by microsomal enzymes. Cytochrome P450 mixed function oxidase, a microsomal enzyme, is one of the most important Phase I enzyme systems. Non-microsomal enzymes catalyze fewer reactions, mainly conjugations, on both foreign and endogenous substances. Although the reaction rate of non-microsomal enzymes cannot be influenced by drugs, the rate of reaction of microsomal enzymes is stimulated by many agents, some inducing their own metabolism as well as that of other agents.
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