Metabolism

Drug metabolism is the phase of biochemical transformation of the drug. It is highly variable among drugs and depends on biological conditions. The metabolism phase is absent for the few drugs that are not transformed. As explained in great detail in other chapters (see 5.05 Principles of Drug Metabolism 1: Redox Reactions; 5.06 Principles of Drug Metabolism 2: Hydrolysis and Conjugation Reactions; 5.07 Principles of Drug Metabolism 3: Enzymes and Tissues; 5.08 Mechanisms of Toxification and Detoxification which Challenge Drug Candidates and Drugs; 5.09 Immuno-toxicology; 5.10 In Vitro Studies of Drug Metabolism; 5.33 Comprehensive Expert Systems to Predict Drug Metabolism; 5.43 Metabonomics), biotransformations may involve one or more successive reactions:

• Phase 1 transformations (reactions of functionalization) involve the creation of a functional group or the modification of an existing one by oxidation, reduction, or hydrolysis.

• Phase 2 transformations (reactions of conjugation) couple a drug or a metabolite to an endogenous conjugating molecule such as glucuronic acid, sulfuric acid, acetic acid, glutathione, etc.

From a physicochemical point of view, drug metabolism is expected to yield metabolites of lower lipophilicity relative to the parent drug, e.g., by adding an ionizable group. As a result, metabolites are often excreted faster than the parent drug, but there are exceptions. From a pharmacological point of view, it is essential to check the pharmacodynamic consequences of these metabolic reactions. Often but far from always, biotransformation involves inactivation or detoxification. Activation concerns prodrugs, but also active compounds (drugs) giving rise to active metabolites. The latter may exhibit a PK profile different from that of the parent drug, and/or a qualitatively different activity. Prodrugs receive specific treatment in Chapters 5.44 and 5.45.

Some enzymes involved in metabolism present a genetic polymorphism, which separates populations of patients according to their phenotypes (i.e., very fast, 'normal,' and poor metabolizers). This is the field of pharmacogenetics. Independently of any pathological state, individuals who are very fast or poor metabolizers need to be identified and have their dosages adjusted.10 Specific monitoring must also be applied for drugs with a low therapeutic index resulting in a low safety margin due to relatively vicinal effective and toxic doses.

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