CYP2C Isoenzyme Metabolism

The CYP2C subfamily consists of 2C9, 2C10, and 2C19 isozymes as well as others. While these enzymes metabolize a smaller number of drugs, many of these drugs are involved in clinically significant DIs. Drugs that are substrates for CYP2C isoenzymes include nonsteroidal anti-inflammatory drugs (NSAIDs) [2C9], phenytoin (2C9), S-warfarin (2C9), amiodarone (2C9), omeprazole and lansoprazole (2C19), and diazepam, clomipramine, amitriptyline and imipramine (2C). Common drugs that are potent inhibitors of 2C9 enzymes include amiodarone, fluvastatin, fluconazole, and omeprazole (2C19), etc. Genetic polymorphism plays a major role with the CYP2C subfamily. Drugs involved with CYP2C are listed in Table 4.

How These Enzymes Modulate Drug–Drug Interactions: Drug interactions can occur when CYP enzymes are either inhibited or induced by certain drugs. Drugs can either significantly enhance or diminish the pharmacologic activity of CYP enzymes.Induction of the gene responsible for producing the enzyme increases the rate of production of the enzyme, thus increasing the cellular content and activity of the induced CYP enzymes. Since enzyme induction involves protein synthesis, there is generally a time delay in both the onset and offset relative to starting and stopping the inducing agent. Therefore, the full effect of the inducing agent may not be evident for several weeks after the inducer drug has been started. The resulting effect will take a similar period of time to fully dissipate after the agent has been discontinued and the rate of enzyme production returns to baseline.

Drug-induced inhibition of CYP enzymes is usually due to competitive binding at enzyme-binding sites and generally occurs within a few hours.The magnitude of inhibition is a function of the concentration of the inhibiting agent. Thus, the half-life of the inhibitor drug will determine how long it must be administered before the full inhibition effect on CYP enzymes is achieved and, conversely, how long after its discontinuation the inhibition phase will endure.

Drug–drug interactions involving CYP isozymes can be either pharmacodynamic or pharmacokinetic in nature. Pharmacodynamic interactions can occur when the mechanism of action of one drug enhances or diminishes the effect produced by the mechanism(s) of action of another drug. Pharmacokinetic interactions can occur when the effect of one drug alters the pharmacokinetic action (e.g., absorption, distribution, metabolism and/or excretion/elimination) of another, leading to a change in its effective concentration at its site(s) of action.

A large number of drug interactions are concentration-dependent, with the risk of the DI increasing with increased plasma levels of these drugs. In patients who receive medications that have a very long elimination half-life (e.g., antidepressants), the time required for the drug to reach steady-state plasma levels can be quite long. This can affect the time course for the onset of clinically significant drug interactions. Using fluoxetine as an example, when taken routinely, it would take approximately one month for it to reach a steady-state level in the bloodstream and cause a drug interaction. Drugs with long half-lives are also generally very slowly metabolized in the body. Consequently, the risk of drug interactions with these drugs may persist for a long period of time after the drug is discontinued. For example, the risk for drug interactions with fluoxetine should be considered for up to six weeks after treatment has been withdrawn. In contrast, venlafaxine has a relatively short half-life of 5–11 hours, it takes 3–5 days to reach a steady-state level, and it may be associated with clinical drug interactions soon after treatment is initiated. In addition, some drugs have nonlinear kinetics, (e.g., fluoxetine and paroxetine), meaning that their concentrations increase to a greater extent than the increase in the parent drug would predict. Because drug interactions are concentration-dependent, higher doses of these medications confer greater risk than might be expected from studies with lower doses. In some instances the metabolite of the parent compound has a greater inhibitory effect on the metabolizing CYP isozyme(s). Thus, the potential for drug interactions may be greater in clinical practice where patients receive doses that are titrated to reach steady state or where they may receive higher initial doses.

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