Pharmacokinetic interactions involving clozapine

Background Metabolism of clozapine is complex and not fully understood. Pharmacokinetic interactions with other drugs have been described but, in some cases, their mechanism is unknown. Method Published trials and case reports relevant to the human metabolism of clozapine and to suspected pharmacokinetic interactions were reviewed. Results Metabolism of clozapine appears to be largely controlled by the function of the hepatic cytochrome p4501A2 (CYP1A2). Compounds which induce CYP1A2 activity (carbamazepine, tobacco smoke) may reduce plasma clozapine levels. inhibitors of CYP1A2 (caffeine, erythromycin) have the opposite effect. Drugs which inhibit the hepatic cytochrome p4502D6 (CYP2D6) have also been reported to elevate plasma clozapine levels. The mechanism of this interaction is unclear. Conclusions The co-administration of clozapine and compounds reported to alter its metabolism should be avoided where possible. A host of other interactions can be predicted and so caution should be exercised when co-administering drugs which affect the function of CYP1A2 and CYP2D6. The pharmacokinetics of clozapine require further investigation so that its safe use can be assured.