CYP-mediated clozapine interactions: how predictable are they?

Despite the introduction of newer drugs, the atypical antipsychotic clozapine remains the most effective drug in psychotic patients who are resistant to treatment with conventional agents. Optimal therapeutic responses to clozapine have been reported with serum concentrations between 350 microg/L and 1000 microg/L. Clozapine is frequently combined with other drugs to enhance efficacy and reduce adverse reactions but pharmacokinetic interactions can have a significant impact on drug response. The majority of the interactions with clozapine are reported to be mediated by cytochrome P450 (CYP) enzymes. CYP1A2 has a major role in the oxidative metabolism of clozapine, with a minor contribution from CYP3A4, and possibly CYP2D6, CYP2C9 and CYP2C19. Interactions mediated by potent CYP1A2 inhibitors (such as fluvoxamine) or inducers (like cigarette smoke) appear to be consistent, predictable and usually clinically significant. There are many case reports of interactions between clozapine and weak CYP1A2 inhibitors or inducers which are also potent inhibitors or inducers of CYP3A4 or CYP2D6. Researchers often explain these observations on the basis of the CYP1A2 involvement. In addition, there are case reports of clinically significant interactions between clozapine and drugs that are not substrates, inhibitors or inducers of CYP1A2. These interactions are difficult to predict and may not be consistent, as reflected by the conflicting literature reports. Further research to elucidate individual differences in clozapine metabolism, with the potential to detect the dominant roles of CYPs other than CYP1A2, may assist us in predicting these interactions.