Hostname: page-component-f554764f5-rj9fg Total loading time: 0 Render date: 2025-04-08T17:44:53.477Z Has data issue: false hasContentIssue false
  • English
  • Français

Pharmacokinetic interactions involving clozapine

Published online by Cambridge University Press:  03 January 2018

David Taylor
David Taylor*
Affiliation:
Maudsley Hospital, London SE5 8AZ
Get access Rights & Permissions [Opens in a new window]

Abstract

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 (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.

Type
Review Article
Information
The British Journal of Psychiatry , Volume 171 , Issue 2 , August 1997 , pp. 109 - 112
Copyright
Copyright © 1997 The Royal College of Psychiatrists 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

REFERENCES

Arranz, M. J., Dawson, E., Shaikh, S., et al (1995) Cytochrome P4502D6 gene type does not determine response to clozapine. British Journal of Clinical Pharmacology, 39, 417–420.CrossRefGoogle Scholar
Bertilsson, L., Carrillo, J. A., Dahl, M. -L., et al (1994) Clozapine disposition covaries with CYPIA2 activity determined by a caffeine test. British Journal of Clinical Pharmacology, 38, 471–473.CrossRefGoogle Scholar
Bertilsson, L., & Dahl, M. -L. (1996) Polymorphic drug oxidation. Relevance to the treatment of psychiatric disorders. CNS Drugs, 5, 200–223.CrossRefGoogle Scholar
Byerly, M. J. & DeVane, C. L. (1996) Pharmacokinetics of clozapine and risperidone: a review of recent literature. Journal of Clinical Psychopharmacology, 16, 177–187.CrossRefGoogle ScholarPubMed
Centorrino, F., Baldessarini, R. J., Kando, J., et al (1994) Serum concentrations of clozapine and its major metabolites: effects of cotreatment with fluoxetine or valproate. American Journal of Psychiatry, 151, 123–125.Google ScholarPubMed
Centorrino, F., Baldessarini, R. J., Frankanburg, F. R., et al (1996) Serum levels of clozapine and norclozapine in patients treated with selective serotonin re-uptake inhibitors. American Journal of Psychiatry, 153, 820–822.Google Scholar
Conney, A. H., Pantuck, E. J., Hsiao, K. C., et al (1976) Enhanced phenacetin metabolism in human subjects fed charcoal-broiled beef. Clinical Pharmacology and Theropeutics, 20, 633–642.CrossRefGoogle ScholarPubMed
Costallo, L. E. & Suppes, T. (1995) A clinically significant interaction between clozapine and valproate. Journal of Clinical Psychopharmacology, 15, 139–141.CrossRefGoogle Scholar
Dahl, M. -L., Lierena, A., Bondesson, U., et al (1994) Disposition of clozapine in man: lack of association with debrisoquine and S-mephenytoin hydroxylation polymorphisms. British Journal of Clinical Pharmacology, 37, 71–74.CrossRefGoogle ScholarPubMed
de Leon, J., Wedlund, P., Ehlers, R., et al (1996) Cytochrome p450-2D6 (CYP2D6) genotype: relationship with clozapine and haloperidol metabolism, Biological Psychiatry, 39, 591.CrossRefGoogle Scholar
Dequardo, J. R. & Roberts, M. (1996) Elevated clozapine levels after fluvoxamme initiation. American Journal of Psychiatry, 6, 840–841.Google Scholar
Dumortier, G., Lochu, A., Colen de Melo, P., et al (1996) Elevated clozapine plasma concentrations after fluvoxamine initiation. American Journal of Psychiatry, 153, 738–739.Google ScholarPubMed
Fischer, V., Vogeis, B., Maurer, G., et al (1992) The antipsychotic clozapine is metabolized by the polymorphic human microsomal and recombinant cytochrome P4502D6. Journal of Pharmacology and Experimental Therapeutics, 260, 1355–1360.Google Scholar
Flanagan, R. J. (1996) Clozapine. Syva Drug Monitor, 2, 5–8.Google Scholar
Funderberg, L. G., Vertrees, J. E., True, J. E., et al (1994) Seizure following addition of erythromycin to clozapine treatment. American Journal of Psychiatry, 151, 1840–1841.Google Scholar
Gerson, S., Arce, C. & Meltzer, H. (1994) N-desmethylclozapine: a clozapine metabolite that suppresses haemoporesis. British Journal of Haematology, 86, 555–561.CrossRefGoogle Scholar
Haring, C., Meise, M., Humpel, C., et al (1989) Dose-related plasma levels of clozapine: influence of smoking behaviour, sex and age. Psychopharmacology, 99. S38–S40.CrossRefGoogle ScholarPubMed
Haring, C., Fleischacker, W. W., Schett, P., et al (1990) Influence of patient-related variables on clozapine levels. American Journal of Psychiatry, 147, 1471–1475.Google Scholar
Haring, C., Neudorfer, C., Schwitzer, J., et al (1994) EEG alterations in patients treated with clozapine in relation to plasma levels. Psychophormocology. 114, 97–100.CrossRefGoogle ScholarPubMed
Harvey, A. T. & Preskorn, S. H. (1996) Cytochrome P450 enzymes: Interpretation of their interactions with selective serotonin re-uptake inhibitors: Part I. Journal of Clinical Psychopharmacology, 16, 273–285.CrossRefGoogle Scholar
Hasegawa, M., Gutierrez-Esteinou, R., Way, L., et al (1993) Relationship between clinical efficacy and clozapine concentrations in plasma in schizophrenia: effect of smoking. Journal of Clinical Psychopharmacology, 13, 383–390.CrossRefGoogle ScholarPubMed
Heykants, J., Huang, M. -L., Mannens, G., et al (1994) The pharmacokinetics of risperidone in humans: A summary. Journal of Clinical Psychiatry, 55 (suppl. 5), 13–17.Google ScholarPubMed
Jann, M. W., Grimsley, S. R., Gray, E. C., et al (1993) Pharmacokinetics and pharmacodynamics of clozapine. Clinical Pharmacokinetics, 24, 161–176.CrossRefGoogle ScholarPubMed
Koponen, H. J., Leinonen, E. & Lepoia, U. (1996) Fluvoxamine increases the clozapine serum levels significantly. European Neuropsychopharmacology, 6, 69–71.CrossRefGoogle ScholarPubMed
Koreen, A. R., Lieberman, J. A., Kronig, M., et al (1995) Cross-tapering clozapine and risperidone. American Journal of Psychiatry, 152, 1690.Google ScholarPubMed
Levy, R. H. (1995) Cytochrome p450 isoenzymes and antiepileptic drug interactions. Epilepsia, 36(suppl. 5). S8–S13.CrossRefGoogle Scholar
Longo, L. P. & Salzman, C. (1995) Valproic acid effects on serum concentrations of clozapine and norclozapine. American Journal of Psychiatry, 152, 650.Google ScholarPubMed
McCarthy, R. H. (1994) Seizures following smoking cessation in a clozapine responder. Pharmacopsychiatry, 27, 210–211.CrossRefGoogle Scholar
Miller, D. D. (1991) Effect of phenytoin on plasma clozapine concentrations in two patients. Journal of Clinical Psychiatry, 52, 23–25.Google ScholarPubMed
Murray, M. (1992) P450 enzymes – inhibition mechanisms, genetic regulation and effects of liver disease. Clinical Pharmacokinetics, 23, 132–146.CrossRefGoogle ScholarPubMed
Nemeroff, C. B., Devane, C. L. & Pollock, B. G. (1996) Newer antidepressants and the cytochrome P450 system. American Journal of Psychiatry, 153, 311–320.Google ScholarPubMed
Odom-White, A. & de Leon, J. (1996) Clozapine levels and caffeine. Journal of Clinical Psychiatry, 57, 175–176.Google ScholarPubMed
Perry, P. J., Miller, D. D., Arndt, S. V., et al (1991) Clozapine and norclozapine plasma concentrations and clinical response of treatment refractory schizophrenic patients. American Journal of Psychiatry, 148, 231–235.Google ScholarPubMed
Pirmohamed, M., Williams, D., Madden, S., et al (1995) Metabolism and bioactivation of clozapine by human liver in vitro. Journal of Pharmacology and Experimental Therapeutics, 272, 984–990.Google ScholarPubMed
Potkin, S. G., Bera, R., Gulasekaram, B., et al (1994) Plasma clozapine concentrations predict clinical response in treatment-resistant schizophrenia. Journal of Clinical Psychiatry, 55 (suppl. B), 133–136.Google ScholarPubMed
Raitasuo, V., Lehtovaara, R. & Huttunen, M. (1996) Carbamazepine and plasma levels of clozapine. American Journal of Psychiatry, 150, 169.Google Scholar
Rosenberry, K. R., Defusco, C. J., Mansmann, H. C., et al (1983) Reduced theophylline half-life induced by carbamazepine therapy. Journal of Paediatrics, 102, 472–474.CrossRefGoogle ScholarPubMed
Schein, J. R. (1995) Cigarette smoking and clinically significant drug interactions. Annals of Pharmacotherapy, 29, 1139–1148.CrossRefGoogle ScholarPubMed
Simpson, G. M. & Cooper, T. A. (1978) Clozapine plasma levels and convulsions. American Journal of Psychiatry, 135, 99–100.Google ScholarPubMed
Slaughter, R. L. & Edwards, D. J. (1995) Recent advances: the cytochrome P450 enzymes. Annals of Pharmacotherapy, 29, 619–624.CrossRefGoogle ScholarPubMed
Szymanski, S., Lieberman, J. A., Picou, D., et al (1991) A case report of cimetidine-induced clozapine toxicity. Journal of Clinical Psychiatry, 52, 21–22.Google ScholarPubMed
Taylor, D. & Duncan, D. (1995) The use of clozapine plasma levels in optimising therapy. Psychiatric Bulletin, 19, 753–755.CrossRefGoogle Scholar
Taylor, D. & Lader, M. (1996) Cytochromes and psychotropic drug interactions. British Journal of Psychiatry, 168, 529–532.CrossRefGoogle ScholarPubMed
Tyson, S. C., Devane, C. L. & Risch, S. C. (1995) Pharmacokinetic interaction between risperidone and clozapine. American Journal of Psychiatry, 152, 1401–1402.Google ScholarPubMed
Wagstaff, A. J. & Bryson, H. M. (1995) Clozapine. A review of its pharmacological properties and therapeutic use in patients with schizophrenia who are unresponsive to or intolerant of classical antipsychotic agents. CNS Drugs, 4, 370–400.CrossRefGoogle Scholar
Williams, D., Magge, M., Pirmohamed, M., et al (1995) Bioactivation of clozapine in vitro and in vivo: implications for drug-induced agranulocytosis. British Journal of Clinical Pharmacology, 40, 182P.Google Scholar
Submit a response

eLetters

No eLetters have been published for this article.