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Titolo:
Effects of CYP2C19 genotype and CYP2C9 on fluoxetine N-demethylation in human liver macrosomes
Autore:
Liu, ZQ; Shu, Y; Huang, SL; Wang, LS; He, N; Zhou, HH;
Indirizzi:
Hunan Med Univ, Pharmacogenet Res Inst, Changsha 410078, Peoples R China Hunan Med Univ Changsha Peoples R China 410078 a 410078, Peoples R China
Titolo Testata:
ACTA PHARMACOLOGICA SINICA
fascicolo: 1, volume: 22, anno: 2001,
pagine: 85 - 90
SICI:
0253-9756(200101)22:1<85:EOCGAC>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
SEROTONIN REUPTAKE INHIBITORS; DRUG-INTERACTIONS; IN-VITRO; ANTIDEPRESSANTS; METABOLISM;
Keywords:
fluoxetine; pharmacokinetics; liver microsomes; cytochrome P-450CYP2C19; cytochrome P-450CYP2C9;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
14
Recensione:
Indirizzi per estratti:
Indirizzo: Zhou, HH Hunan Med Univ, Pharmacogenet Res Inst, Changsha 410078, Peoples R China Hunan Med Univ Changsha Peoples R China 410078 Peoples R China
Citazione:
Z.Q. Liu et al., "Effects of CYP2C19 genotype and CYP2C9 on fluoxetine N-demethylation in human liver macrosomes", ACT PHAR SI, 22(1), 2001, pp. 85-90

Abstract

AIM: The present study was designed to define the kinetic behavior of fluoxetine N-demethylation in human liver microsomes and to identify the isoforms of cytochrome P-450 (CYP) involved in this metabolic pathway. METHODS: The kinetics of the formation of norfluoxetine was determined in human livermicrosomes from six genotyped CYP2C19 extensive metabolizers (EM). The correlation studies between the fluoxetine N-demethylase activity and various CYP enzyme activities were performed. Selective inhibitors or chemical probes of various cytochrome P-450 isoforms were also employed. RESULTS: The kinetics of norfluoxetine formation in all liver microsomes were fitted by a single-enzyme Michaelis-Menten equation (mean K-m = 32 mu mol/L +/- 7 mu mol/L). Significant correlations were found between N-demethylation of fluoxetine at both 25 mu mol/L and 100 mu mol/L and 3-hydroxylation of tolbutamide at 250 mu mol/L ( r(1) = 0.821, P-1 = 0.001; r(2) = 0.668, P-2 = 0.013), respectively, and S-mephenytoin 4'-hydroxylase activity (r = 0.717, P = 0.006) at high substrate concentration of 100 mu mol/L. S-mephenytoin (SMP) (aCYP2C19 substrate) at high concentration and sulfaphenazole (SUL) (a selective inhibitor of CYP2C9) substantially inhibited norfluoxetine formation. The reaction was minimally inhibited by coincubation with chemical probe, inhibitor of CYP3A4 (triacetyloleandomycin, TAO). The inhibition of fluoxetine N-demethylation at high substrate concentration (100 mu mol/L) was greater in PM livers than in EM livers (73 % vs 45 %, P < 0.01) when the microsomes were precoincubated with SUL plus TAO. CONCLUSION: Cytochrome P-450 CYP2C9 is likely to be a major CYP isoform catalyzing fluoxetine N-demethylation in human liver microsomes at a substrate concentration close to the therapeutic level, while polymorphic CYP2C19 may play a more important role in this metabolic pathway at high substrate concentration.

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Documento generato il 28/01/20 alle ore 15:16:43