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Titolo:
Different enantioselective 9-hydroxylation of risperidone by the two humanCYP2D6 and CYP3A4 enzymes
Autore:
Yasui-Furukori, N; Hidestrand, M; Spina, E; Facciola, G; Scordo, MG; Tybring, G;
Indirizzi:
Huddinge Univ Hosp, Karolinska Inst, Div Clin Pharmacol, Dept Med Lab Sci & Technol, SE-14186 Stockholm, Sweden Huddinge Univ Hosp Stockholm SwedenSE-14186 SE-14186 Stockholm, Sweden Karolinska Inst, Dept Environm Med, Div Mol Toxicol, Stockholm, Sweden Karolinska Inst Stockholm Sweden ed, Div Mol Toxicol, Stockholm, Sweden Univ Messina, Pharmacol Sect, Dept Clin & Expt Med & Pharmacol, Messina, Italy Univ Messina Messina Italy Clin & Expt Med & Pharmacol, Messina, Italy
Titolo Testata:
DRUG METABOLISM AND DISPOSITION
fascicolo: 10, volume: 29, anno: 2001,
pagine: 1263 - 1268
SICI:
0090-9556(200110)29:10<1263:DE9ORB>2.0.ZU;2-G
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN LIVER-MICROSOMES; CYTOCHROMES P450 2D6; IN-VITRO; 9-HYDROXYRISPERIDONE; METABOLISM; PLASMA; HYDROXYLATION; NORTRIPTYLINE; DRUGS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
28
Recensione:
Indirizzi per estratti:
Indirizzo: Tybring, G Huddinge Univ Hosp, Karolinska Inst, Div Clin Pharmacol, Dept Med Lab Sci & Technol, SE-14186 Stockholm, Sweden Huddinge Univ Hosp Stockholm Sweden SE-14186 tockholm, Sweden
Citazione:
N. Yasui-Furukori et al., "Different enantioselective 9-hydroxylation of risperidone by the two humanCYP2D6 and CYP3A4 enzymes", DRUG META D, 29(10), 2001, pp. 1263-1268

Abstract

The antipsychotic agent risperidone, is metabolized by different cytochrome P-450 (CYP) enzymes, including CYP2D6, to the active 9-hydroxyrisperidone, which is the major metabolite in plasma. Two enantiomers, (+)- and (-)-9-hydroxyrisperidone might be formed, and the aim of this study was to evaluate the importance of CYP2D6 and CYP3A4/CYP3A5 in the formation of these twoenantiomers in human liver microsomes and in recombinantly expressed enzymes. The enantiomers of 9-hydroxyrisperidone were analyzed with high pressure liquid chromatography using a chiral alpha -1 acid glycoprotein column. Amuch higher formation rate was observed for (+)-9-hydroxyrisperidone than for (-)-9-hydroxyrisperidone in microsomes prepared from six individual livers. The formation of (+)-9-hydroxyrisperidone was strongly inhibited by quinidine, a potent CYP2D6 inhibitor, whereas ketoconazole, a CYP3A4 inhibitor, strongly inhibited the formation of (-)-9-hydroxyrisperidone. Recombinant human CYP2D6 produced only (+)-9-hydroxyrisperidone, whereas a lower formation rate of both enantiomers was detected with expressed CYP3A4 and CYP3A5. In vivo data from 18 patients during treatment with risperidone indicatethat the plasma concentration of the (+)-enantiomer is higher than that ofthe (-)-enantiomer in extensive metabolizers of CYP2D6. These findings clearly suggest that CYP2D6 plays a predominant role in (+)-9-hydroxylation ofrisperidone, the major metabolic pathway in clinical conditions, whereas CYP3A catalyzes the formation of the (-)-9-hydroxymetabolite. Further studies are required to evaluate the pharmacological/toxic activity of both enantiomers.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 19/01/20 alle ore 07:05:50