Characterization of human cytochrome P450 enzymes involved in the in vitro metabolism of perospirone
- PMID:15619261
- DOI: 10.1002/bdd.432
Characterization of human cytochrome P450 enzymes involved in the in vitro metabolism of perospirone
Abstract
In vitro studies were carried out to identify the major contribution of CYP2C8, CYP2D6 and CYP3A4 to the metabolism of perospirone (cis-N-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]cyclohexane-1,2-dicarboximide monohydrochloride dehydrate), a novel antipsychotic agent, using human liver microsomes and expressed P450 isoforms. Quinidine (a specific inhibitor of CYP2D6) did not markedly affect the metabolism of perospirone, whereas quercetin (an inhibitor of CYP2C8) and ketoconazole (an inhibitor of CYP3A4) caused a decrease in the metabolism with human liver microsomes in a concentration dependent fashion. With 10 microM quercetin, the metabolism of perospirone was inhibited by 60.0% and with 1 microM ketoconazole almost complete inhibition was apparent. Anti-CYP2C8 and anti-CYP2D6 antisera did not exert marked effects, whereas anti-CYP3A4 antiserum caused almost complete inhibition. With expressed P450s, K(m) and V(max) values were 1.09 microM and 1.93 pmol/min/pmol P450 for CYP2C8, 1.38 microM and 5.73 pmol/min/pmol P450 for CYP2D6, and 0.245 microM and 61.3 pmol/min/pmol P450 for CYP3A4, respectively. These results indicated that the metabolism of perospirone in human liver was mainly catalysed by CYP3A4, and to a lesser extent CYP2C8 and CYP2D6 were responsible because kinetic data (K(m) and V(max)) of CYP2C8 and CYP2D6 suggested catalytic potential.
Copyright 2004 John Wiley & Sons, Ltd.
Similar articles
- Interaction of cisapride with the human cytochrome P450 system: metabolism and inhibition studies.Desta Z, Soukhova N, Mahal SK, Flockhart DA.Desta Z, et al.Drug Metab Dispos. 2000 Jul;28(7):789-800.Drug Metab Dispos. 2000.PMID:10859153
- Metabolism of the antidepressant mirtazapine in vitro: contribution of cytochromes P-450 1A2, 2D6, and 3A4.Störmer E, von Moltke LL, Shader RI, Greenblatt DJ.Störmer E, et al.Drug Metab Dispos. 2000 Oct;28(10):1168-75.Drug Metab Dispos. 2000.PMID:10997935
- In vitro metabolism of simvastatin in humans [SBT]identification of metabolizing enzymes and effect of the drug on hepatic P450s.Prueksaritanont T, Gorham LM, Ma B, Liu L, Yu X, Zhao JJ, Slaughter DE, Arison BH, Vyas KP.Prueksaritanont T, et al.Drug Metab Dispos. 1997 Oct;25(10):1191-9.Drug Metab Dispos. 1997.PMID:9321523
- Metabolism of atypical antipsychotics: involvement of cytochrome p450 enzymes and relevance for drug-drug interactions.Urichuk L, Prior TI, Dursun S, Baker G.Urichuk L, et al.Curr Drug Metab. 2008 Jun;9(5):410-8. doi: 10.2174/138920008784746373.Curr Drug Metab. 2008.PMID:18537577Review.
- Pharmacokinetics of haloperidol: an update.Kudo S, Ishizaki T.Kudo S, et al.Clin Pharmacokinet. 1999 Dec;37(6):435-56. doi: 10.2165/00003088-199937060-00001.Clin Pharmacokinet. 1999.PMID:10628896Review.
Cited by
- Effect of the novel antipsychotic drug perospirone on P-glycoprotein function and expression in Caco-2 cells.Zhou YG, Li KY, Li HD.Zhou YG, et al.Eur J Clin Pharmacol. 2008 Jul;64(7):697-703. doi: 10.1007/s00228-008-0487-5. Epub 2008 May 14.Eur J Clin Pharmacol. 2008.PMID:18478216
- Identification of CYP3A4 as the primary cytochrome P450 responsible for the metabolism of tandospirone by human liver microsomes.Natsui K, Mizuno Y, Tani N, Yabuki M, Komuro S.Natsui K, et al.Eur J Drug Metab Pharmacokinet. 2007 Jul-Sep;32(3):131-7. doi: 10.1007/BF03190475.Eur J Drug Metab Pharmacokinet. 2007.Retraction in:Eur J Drug Metab Pharmacokinet. 2019 Dec;44(6):853. doi: 10.1007/s13318-019-00585-5.PMID:18062405Retracted.
- Identification of CYP3A4 as the primary cytochrome P450 responsible for the metabolism of tandospirone by human liver microsomes.Natsui K, Mizuno Y, Tani N, Yabuki M, Komuro S.Natsui K, et al.Eur J Drug Metab Pharmacokinet. 2007 Oct-Dec;32(4):233-40. doi: 10.1007/BF03191009.Eur J Drug Metab Pharmacokinet. 2007.PMID:18348473
MeSH terms
Substances
Related information
LinkOut - more resources
Full Text Sources