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Titolo:
Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4
Autore:
Fang, J; Bourin, M; Baker, GB;
Indirizzi:
Univdalberta, Dept Psychiat, Neurochem Res Unit, Edmonton, AB T6G 2B7, Cana Univ Alberta Edmonton AB Canada T6G 2B7 Unit, Edmonton, AB T6G 2B7, Cana Univ Nantes, Pharmacol Lab, Nantes, France Univ Nantes Nantes FranceUniv Nantes, Pharmacol Lab, Nantes, France
Titolo Testata:
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
fascicolo: 2, volume: 359, anno: 1999,
pagine: 147 - 151
SICI:
0028-1298(199902)359:2<147:MORT9B>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
PHARMACOKINETICS; OXIDATION; EXCRETION;
Keywords:
risperidone; 9-hydroxyrisperidone; CYP2D6; CYP3A4; drug metabolism;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
17
Recensione:
Indirizzi per estratti:
Indirizzo: Fang, J Univoon,katchewan, Coll Pharm & Nutr, Drug Disposit Grp, 110 Sci Pl, Saskat Univ Saskatchewan 110 Sci Pl Saskatoon SK Canada S7N 5C9 l, Saskat
Citazione:
J. Fang et al., "Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4", N-S ARCH PH, 359(2), 1999, pp. 147-151

Abstract

Risperidone is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia andproduces relatively few extrapyramidal side effects at low doses. Formation of 9-hydroxyrisperidone, an active metabolite, is the most important metabolic pathway of risperidone in human. In the present study, in vitro metabolism of risperidone (100 mu M) was investigated using the recombinant human cytochrome P450 (CYP) enzymes CYP1A1, CYP1A2, CYP2C8, CYP2C9-arg(144), CYP2C9-cys(144), CYP2C19, CYP2D6, CYP3A4 and CYP3A5 supplemented with an NADPH-generating system. 9-Hydroxyrisperidone was determined by a new HPLC method with an Hypersil CN column and a UV detector. Of these enzymes, CYPs 2D6, 3A4 and 3A5 were found to be the ones capable of metabolising risperidoneto 9-hydroxyrisperidone, with activities of 7.5, 0.4 and 0.2 pmol pmol(-1)CYP min(-1), respectively. A correlation study using a panel of human liver microsomes showed that the formation of 9-hydroxyrisperidone is highly correlated with CYP2D6 and 3A activities. Thus, both CYP2D6 and 3A4 are involved in the 9-hydroxylation of risperidone at the concentration of risperidone used in this study. This observation is confirmed by the findings that both quinidine (inhibitor of CYP2D6) and ketoconazole (inhibitor of CYP3A4) can inhibit the formation of 9-hydroxyrisperidone. Furthermore, inducers ofCYP can significantly increase the formation of 9-hydroxyrisperidone in rat. The formation of 9-hydroxyrisperidone is highly correlated with testosterone 6 beta-hydroxylase activities, suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 25/01/20 alle ore 19:39:39