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 p450IA2 (CYPIA2). Compounds which induce CYPIA2 activity (carbamazepine, tobacco smoke) may reduce plasma clozapine levels. Inhibitors of CYPIA2 (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 CYPIA2 and CYP2D6. The pharmacokinetics of clozapine require further investigation so that its safe use can be assured.