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Titolo:
HUMAN N-DEMETHYLATION OF (S)-MEPHENYTOIN BY CYTOCHROME P450S 2C9 AND 2B6
Autore:
KO JW; DESTA Z; FLOCKHART DA;
Indirizzi:
GEORGETOWN UNIV,MED CTR,DIV CLIN PHARMACOL,DEPT MED,3900 RESERVOIR RDNW WASHINGTON DC 20007 GEORGETOWN UNIV,MED CTR,DIV CLIN PHARMACOL,DEPT MED WASHINGTON DC 20007 GEORGETOWN UNIV,MED CTR,DEPT PHARMACOL WASHINGTON DC 20007
Titolo Testata:
Drug metabolism and disposition
fascicolo: 8, volume: 26, anno: 1998,
pagine: 775 - 778
SICI:
0090-9556(1998)26:8<775:HNO(BC>2.0.ZU;2-V
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-LIVER-MICROSOMES; MEPHENYTOIN HYDROXYLATION DEFICIENCY; METABOLISM; FLUCONAZOLE; INHIBITION; ASSAY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
21
Recensione:
Indirizzi per estratti:
Citazione:
J.W. Ko et al., "HUMAN N-DEMETHYLATION OF (S)-MEPHENYTOIN BY CYTOCHROME P450S 2C9 AND 2B6", Drug metabolism and disposition, 26(8), 1998, pp. 775-778

Abstract

We tested the ability of human liver microsomes (HLMs) and recombinant human cytochrome P450 (CYP or P450) isoforms to catalyze the N-demethylation of nirvanol-free (S)-mephenytoin [(S)-MP] in vitro. In mixed HLMs, the kinetics of (S)-MP N-demethylation suggested two contributing activities. A high-affinity/low-capacity component exhibited a K-M of 174.1 mu M and a V-max of 170.5 pmol/mg protein/min, whereas a low-affinity/high-capacity component exhibited a K-M of 1911 mu M and a V-max of 3984 pmol/mg protein/min. The activity of the high-affinity component was completely abolished by sulfaphenazole, with little effect on the low-affinity component. Of the recombinant P450 isoforms tested,only CYP2B6 and CYP2C9 formed nirvanol from (S)-MP. The K-M value (150 +/- 42 mu M) derived for recombinant CYP2C9 was close to that obtained for the high-affinity/low-capacity component in mixed HLMs (K-M = 174.1 mu M). The predicted contribution of this activity at concentrations (1-25 mu M) achieved after a single 100-mg dose of racemic MP is approximately 30% of the rate of nirvanol formation, At concentrations of >1000 mu M, we estimate that >90% of the rate can be explained by the low-affinity activity (CYP2B6). Therefore, the N-demethylation of (S)-MP to nirvanol may be a useful means of probing the activity of CYP2B6 in vitro when concentrations of >1000 mu M are used, but it is unlikely to be a suitable phenotyping tool for this isoform in vivo, where concentrations of >1000 mu M are rarely encountered.

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Documento generato il 18/01/20 alle ore 21:30:53