Interactions Between the Cytochrome P450 System and the Second-generation Antipsychotics

Overview

Journal J Psychiatry Neurosci

Specialty Psychiatry

Date 2003 Apr 3

PMID 12670127

Citations 51

Authors

Trevor I Prior

Glen B Baker

Affiliations

Soon will be listed here.

Abstract

Awareness of the metabolism of second-generation antipsychotics by the cytochrome P450 (CYP) system can inform the clinician about how to avoid and manage drug-drug interactions involving these enzymes. Clozapine is metabolized primarily by CYP1A2, with additional contributions by CYP2C19, CYP2D6 and CYP3A4. Risperidone is metabolized primarily by CYP2D6 and to a lesser extent by CYP3A4. Olanzapine is metabolized primarily by CYP1A2 and to a lesser extent by CYP2D6. Quetiapine and ziprasidone are metabolized by CYP3A4. At the usual clinical doses, these drugs appear not to significantly affect the metabolism of other medications. There is, however, a lack of in vivo metabolic data, especially for the 3 newest second-generation antipsychotics: olanzapine, quetiapine and ziprasidone.

Citing Articles

Reactivity of Olanzapine and Tricyclic Antidepressants on the Protective Effects of Trolox on Lipid Peroxidation Evaluated Using Fluorescence Anisotropy, Electron Paramagnetic Resonance Spectrometry, and Thermal Analysis.

Horizumi Y, Tanada R, Kurosawa Y, Takatsuka M, Tsuchida T, Goto S ACS Chem Neurosci. 2025; 16(3):462-478.

PMID: 39818700 PMC: 11809279. DOI: 10.1021/acschemneuro.4c00702.

Clozapine and Pneumonia: Synthesizing the Link by Reviewing Existing Reports-A Systematic Review and Meta-Analysis.

Zhao V, Gong Y, Thomas N, Das S Medicina (Kaunas). 2025; 60(12.

PMID: 39768896 PMC: 11728434. DOI: 10.3390/medicina60122016.

Alert prescribing of clozapine: a comparison of five drug-drug interaction sources.

Govaerts J, Verluyten A, Bouckaert F, De Hert M, Desplenter F Ther Adv Drug Saf. 2024; 15:20420986241233842.

PMID: 39629024 PMC: 11613245. DOI: 10.1177/20420986241233842.

Olanzapine use for the treatment of adolescents with anorexia nervosa - reflecting on research and clinical practice.

Spettigue W, Norris M J Can Acad Child Adolesc Psychiatry. 2024; 33(3):164-170.

PMID: 39534775 PMC: 11552675.

Expert Consensus on the Management of Adverse Events of Lorlatinib in the Treatment of ALK+ Advanced Non-small Cell Lung Cancer.

Arriola E, de Castro J, Garcia-Campelo R, Bernardez B, Bernabe R, Bruna J Clin Drug Investig. 2024; 44(8):553-576.

PMID: 39085682 PMC: 11338981. DOI: 10.1007/s40261-024-01379-7.

References

Shen W . The metabolism of psychoactive drugs: a review of enzymatic biotransformation and inhibition. Biol Psychiatry. 1997; 41(7):814-26. DOI: 10.1016/S0006-3223(96)00180-1. View

Koponen H, Leinonen E, Lepola U . Fluvoxamine increases the clozapine serum levels significantly. Eur Neuropsychopharmacol. 1996; 6(1):69-71. DOI: 10.1016/0924-977x(95)00069-2. View

Mannens G, Huang M, Meuldermans W, Hendrickx J, Woestenborghs R, Heykants J . Absorption, metabolism, and excretion of risperidone in humans. Drug Metab Dispos. 1993; 21(6):1134-41. View

Wilner K, Demattos S, Anziano R, Apseloff G, Gerber N . Ziprasidone and the activity of cytochrome P450 2D6 in healthy extensive metabolizers. Br J Clin Pharmacol. 2000; 49 Suppl 1:43S-47S. PMC: 2015060. DOI: 10.1046/j.1365-2125.2000.00152.x. View

De Leon J, Bork J . Risperidone and cytochrome P450 3A. J Clin Psychiatry. 1997; 58(10):450. DOI: 10.4088/jcp.v58n1010b. View

Seppala N, Leinonen E, Lehtonen M, Kivisto K . Clozapine serum concentrations are lower in smoking than in non-smoking schizophrenic patients. Pharmacol Toxicol. 1999; 85(5):244-6. DOI: 10.1111/j.1600-0773.1999.tb02016.x. View

Taylor D . Pharmacokinetic interactions involving clozapine. Br J Psychiatry. 1997; 171:109-12. DOI: 10.1192/bjp.171.2.109. View

Dev V, Raniwalla J . Quetiapine: a review of its safety in the management of schizophrenia. Drug Saf. 2000; 23(4):295-307. DOI: 10.2165/00002018-200023040-00003. View

Lin J, Lu A . Inhibition and induction of cytochrome P450 and the clinical implications. Clin Pharmacokinet. 1998; 35(5):361-90. DOI: 10.2165/00003088-199835050-00003. View

10.

Hedlund E, Wyss A, Kainu T, Backlund M, Kohler C, Pelto-Huikko M . Cytochrome P4502D4 in the brain: specific neuronal regulation by clozapine and toluene. Mol Pharmacol. 1996; 50(2):342-50. View

11.

Jerling M, Merle Y, Mentre F, Mallet A . Population pharmacokinetics of clozapine evaluated with the nonparametric maximum likelihood method. Br J Clin Pharmacol. 1998; 44(5):447-53. PMC: 2042877. DOI: 10.1046/j.1365-2125.1997.t01-1-00606.x. View

12.

Bertz R, Granneman G . Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet. 1997; 32(3):210-58. DOI: 10.2165/00003088-199732030-00004. View

13.

Spina E, Avenoso A, Facciola G, Scordo M, Ancione M, Madia A . Plasma concentrations of risperidone and 9-hydroxyrisperidone during combined treatment with paroxetine. Ther Drug Monit. 2001; 23(3):223-7. DOI: 10.1097/00007691-200106000-00007. View

14.

Miceli J, Smith M, Robarge L, Morse T, Laurent A . The effects of ketoconazole on ziprasidone pharmacokinetics--a placebo-controlled crossover study in healthy volunteers. Br J Clin Pharmacol. 2000; 49 Suppl 1:71S-76S. PMC: 2015056. DOI: 10.1046/j.1365-2125.2000.00156.x. View

15.

Olesen O, Licht R, THOMSEN E, Bruun T, Viftrup J, Linnet K . Serum concentrations and side effects in psychiatric patients during risperidone therapy. Ther Drug Monit. 1998; 20(4):380-4. DOI: 10.1097/00007691-199808000-00004. View

16.

Prakash C, Kamel A, Cui D, Whalen R, Miceli J, Tweedie D . Identification of the major human liver cytochrome P450 isoform(s) responsible for the formation of the primary metabolites of ziprasidone and prediction of possible drug interactions. Br J Clin Pharmacol. 2000; 49 Suppl 1:35S-42S. PMC: 2015052. DOI: 10.1046/j.1365-2125.2000.00151.x. View

17.

Wietholtz H, Zysset T, Marschall H, Generet K, Matern S . The influence of rifampin treatment on caffeine clearance in healthy man. J Hepatol. 1995; 22(1):78-81. DOI: 10.1016/0168-8278(95)80263-0. View

18.

Hiratsuka M, Mizugaki M . Genetic polymorphisms in drug-metabolizing enzymes and drug targets. Mol Genet Metab. 2001; 73(4):298-305. DOI: 10.1006/mgme.2001.3204. View

19.

Meisel C, Roots I, Cascorbi I, Brinkmann U, Brockmoller J . How to manage individualized drug therapy: application of pharmacogenetic knowledge of drug metabolism and transport. Clin Chem Lab Med. 2000; 38(9):869-76. DOI: 10.1515/CCLM.2000.126. View

20.

Yasui-Furukori N, Hidestrand M, Spina E, Facciola G, Scordo M, Tybring G . Different enantioselective 9-hydroxylation of risperidone by the two human CYP2D6 and CYP3A4 enzymes. Drug Metab Dispos. 2001; 29(10):1263-8. View