Cytochrome P450 and therapeutic drug monitoring with respect to clozapine

Clozapine is an atypical antipsychotic drug that is mainly used for the tre atment of refractory schizophrenia. Clozapine is eliminated by oxidation in the liver, predominantly by cytochrome P4501A2 (CYP1A2). Due to the influe nce of inhibitors, inducers and genetic factors on CYP1A2-activity, several studies have reported a very large interindividual variability in clozapin e plasma concentrations at a fixed dose. A number of methods have been publ ished for the measurement of clozapine and metabolites in plasma. Plasma co ncentrations are most frequently measured by high-performance liquid chroma tography. Most methods measure clozapine and the main metabolite, norclozap ine, whereas two methods measure clozapine and two metabolites. Several stu dies suggest that a minimum effective clozapine plasma concentration of >35 0 mu g/1 must be achieved in order to ensure acceptable clinical response, whereas the upper limit of the therapeutic interval not yet has been clearl y defined. The occurrence of agranulocytosis, the most serious side-effect of clozapine treatment does not seem to be dose-related and it is not possi ble to predict which patients are at risk of developing agranulocytosis. Th e risk of central nervous system side-effects seems to increase with concen trations above 1300 mu g/l. Monitoring of clozapine plasma concentrations i s recommended during concomitant use of other drugs that are known to inter act with the oxidation of clozapine, such as carbamazepine (inducer) or flu voxamine (inhibitor). Overall, it is concluded that therapeutic drug monito ring may be of value in the clinical management of clozapine. (C) 1999 Else vier Science B.V. All rights reserved.