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Table 49–1 shows the pharmacokinetic properties of selected second-generation antipsychotics (SGAs) and selected first-generation antipsychotics (FGAs). Knowledge about specific cytochrome P450 (CYP) enzymes that metabolize antipsychotics is important in predicting and managing potential drug-drug interactions. Six CYP enzymes located in the brain and the periphery are responsible for approximately 90% of all the CYP activity (Meyer 2007). Whenever medications are metabolized by the same liver enzyme, the competition can lead to increased serum levels of both drugs. Conversely, medications, nutraceuticals, and smoking that can induce CYP enzyme production may lower antipsychotic serum levels. The CYP enzymes 3A4, 2D6, and 1A2 are most important for antipsychotic clearance. CYP3A4 is a low-affinity, high-capacity enzyme, making it relatively immune to saturation, unless very potent inhibitors are present. CYP3A4 is mainly relevant for haloperidol, quetiapine, and olanzapine clearance. The CYP2D6 is a high-affinity, low-capacity enzyme. It is very efficient and not readily inducible, but it can be saturated more easily (Meyer 2007). Moreover, most known genetic polymorphisms affect CYP2D6. Aripiprazole, molindone, perphenazine, and risperidone are predominantly cleared by CYP2D6. The CYP1A2 enzyme is also a low-affinity, high-capacity enzyme and is relevant for the clearance of clozapine and, to some degree, of olanzapine. The CYP2C19 and 2C9 are only relevant for clozapine clearance. In addition, the aldehyde oxidase system, which is neither saturable nor inhibitable, is responsible for 67% of ziprasidone's metabolism. Since <10% of paliperidone and only 33% of ziprasidone are undergoing CYP first-pass metabolism, the likelihood of drug-drug interactions is lowest with these two antipsychotics. Updated CYP450 interactions are available at: http://medicine.iupui.edu/flockhart/table.htm.

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Table Reference Number
TABLE 49–1. Pharmacokinetic information for first- and second-generation antipsychotics
Table Reference Number
TABLE 49–2. Therapeutic and adverse effects of antipsychotic receptor occupancy and abrupt withdrawal

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