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Human N-demethylation of (S)-mephenytoin by cytochrome P450s 2C9 and 2B6.
Ko, J W; Desta, Z; Flockhart, D A.
Afiliação
  • Ko JW; Division of Clinical Pharmacology, Department of Medicine, Georgetown University Medical Center, Washington, DC 20007, USA.
Drug Metab Dispos ; 26(8): 775-8, 1998 Aug.
Article em En | MEDLINE | ID: mdl-9698292
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 KM of 174.1 microM and a Vmax of 170.5 pmol/mg protein/min, whereas a low-affinity/high-capacity component exhibited a KM of 1911 microM and a Vmax 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 KM value (150 +/- 42 microM) derived for recombinant CYP2C9 was close to that obtained for the high-affinity/low-capacity component in mixed HLMs (KM = 174.1 microM). The predicted contribution of this activity at concentrations (1-25 microM) achieved after a single 100-mg dose of racemic MP is approximately 30% of the rate of nirvanol formation. At concentrations of >1000 microM, 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 microM are used, but it is unlikely to be a suitable phenotyping tool for this isoform in vivo, where concentrations of >1000 microM are rarely encountered.
Assuntos
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxirredutases N-Desmetilantes / Esteroide Hidroxilases / Hidrocarboneto de Aril Hidroxilases / Sistema Enzimático do Citocromo P-450 / Esteroide 16-alfa-Hidroxilase / Mefenitoína / Anticonvulsivantes Limite: Humans Idioma: En Revista: Drug Metab Dispos Ano de publicação: 1998 Tipo de documento: Article
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Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oxirredutases N-Desmetilantes / Esteroide Hidroxilases / Hidrocarboneto de Aril Hidroxilases / Sistema Enzimático do Citocromo P-450 / Esteroide 16-alfa-Hidroxilase / Mefenitoína / Anticonvulsivantes Limite: Humans Idioma: En Revista: Drug Metab Dispos Ano de publicação: 1998 Tipo de documento: Article