Cytochrome P450 enzymes antidepressant drugs

In this chapter, we have discussed the mechanisms of action of the major antidepressant drugs. The acute pharmacological actions of these agents on receptors and enzymes have been described, as well as the major hypothesis that attempts to explain how all current antidepressants ultimately work. That hypothesis is known as the neurotransmitter receptor hypothesis of antidepressant action. We have also introduced pharmacokinetic concepts relating to the metabolism of antidepressants and mood stabilizers by the cytochrome P450 enzyme system. 

Another cytochrome P450 enzyme of importance to atypical antipsychotic drugs is 2D6. Risperidone, clozapine, and olanzapine are all substrates for this enzyme (Fig. 11—46). Risperidone s metabolite is also an active atypical antipsychotic (Fig. 11 — 47), but the metabolites of clozapine and olanzapine are not. Recall that some antidepressants are inhibitors of CYP450 2D6 and thus can raise the levels of these... 

Pharmacokinetic interactions. TCAs and SSRIs are metabolised extensively by cytochrome P450 enzymes and adding, changing or stopping antidepressants to a drug regimen can have important consequences. 

Shin J-G, Park J-Y, Kim M-J, Shon J-H, Yoon Y-R, Cha I-J, Lee S-S, Oh S-W, Kim S-W, Flockhart DA. Inhibitory effects of tricyclic antidepressants (TCAs) on human cytochrome P450 enzymes in vitro mechanism of drug interaction between TCAs and phenytoin. Drug Metab Dispos (2002) 30, 1102-7. 

The ability of an SSRI, or any antidepressant, to inhibit or induce the activity of the cytochrome P450 (CYP450) enzymes can be a significant contributory factor in determining its capability to cause a pharmacokinetic drug-drug interaction. 

Drug Interactions. No modern discussion of the history of antidepressants would be complete without mention of the debate regarding potential drug interactions. As discussed more fully in Chapter 2, medications may interact in several ways, and their interactions may be helpful or harmful. The antidepressant debate has focused on the way these drugs influence the liver s ability to metabolize and thus deactivate other drugs. In particular, it is the impact of antidepressants on the liver s cytochrome P450 family of enzymes that has been so extensively discussed. 

The cytochrome P450 system is actually a family of related liver enzymes. Each specific enzyme within this family is called an isoenzyme. New isoenzymes within the cytochrome P450 system are constantly being discovered. The 1A2, 2C9/2C19, 2D6, and 3A4 isoenzymes are the best understood. Table 3.10 shows the impact of the newer antidepressants on particular cytochrome P450 isoenzymes and the drugs that may be affected. 

Methylphenidate is an inhibitor of drug metabolizing enzymes of the cytochrome P450 family and several interactions with drugs like some antiepileptics, antidepressants and oral anticoagulants, have been described. 

FIGURE 11-44. Clozapine and olanzapine are substrates for cytochrome P450 1A2 (CYP450 1A2). When these drugs are given with an inhibitor of this enzyme, such as the antidepressant fluvoxamine, plasma levels of olanzapine and clozapine can rise. 

Potential interactions through the cytochrome P450 CYP 2D6 and CYP 3A4 enz)unes can be noted from Tables 19.2a and 19.2b. The combination of drugs that are substrates of the same enzyme creates potential for competitive inhibition of their metabolism with unexpected elevation of plasma concentration. Similarly, potent inhibitors, e.g. fluoxetine and paroxetine (CYP 2D6), fluoxetine and nefazodone (CYP 3A4) and fluvoxamine (CYP 1A2), may cause adverse effects by reducing metabolic breakdown of co-prescribed drugs that are used in standard doses. Antidepressants are commonly prescribed with antipsychotics in a depressive... 

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