Metabolism

Interaction between two drugs that affect the metabolism of one or both can be clinically important. Drugs can be inducers or inhibitors of metabolizing enzymes. Pharmacokinetic interactions for small molecules can be biotransformation and/or transporter based.

Biotransformation-based drug-drug interactions may occur because of the presence of cytochrome P (CYP)450 system (1). High concentrations of these enzymes are located in the liver and small intestine. The concentrations of CYP450 system can be altered by inhibition and induction and can vary from person to person. Many drugs may increase or decrease the activity of various CYP isozymes, which may result in adverse drug interactions, since changes in CYP enzyme activity may affect the metabolism and clearance of various drugs.

Transporter-based drug-drug interactions play an important role in the processes of drug absorption, distribution, and excretion (6). Because of these characteristics, transporters are involved in clinically significant transportermediated drug interactions. The ultimate result of such interactions is alteration in the efficacy or safety of a given drug (the substrate). Transporter-mediated drug interaction with macromolecules has not been established.

It is widely believed that therapeutic proteins are metabolized by the same catabolic pathways as endogenous proteins and are broken down into amino acid fragments (7). Generally, the metabolic products of proteins are not considered as a safety risk. Compared with conventional small-molecule drugs, characterizing the metabolites of therapeutic proteins is a much more difficult task. These difficulties arise because of the lack of suitable analytical method(s) and abundance of potential sites of metabolism (because of the complex structure of therapeutic proteins). Most proteins are catabolized by proteolysis via enzymes distributed throughout the body. Proteolytic activity at a site of injection can lead to protein degradation after SC administration (7). Furthermore, the rate and extent of production of the metabolites will depend on the route of administration. Although therapeutic proteins and monoclonal antibodies may not be metabolized by the CYP450 system, they can inhibit or stimulate the CYP450 system in the body (8).

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