Pharmacokinetic Considerations | Pharmacodynamic Considerations | Pharmacokinetic and Pharmacodynamic Rebound Phenomena
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.