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Interaction between 3,4­dichlorophenyl­propenoyl­sec.­butylamine (3,4­DCPB), an antiepileptic drug, and cytochrome P450 in rat liver microsomes and recombinant human enzymes in vitro.
Cheng, Hai-Xu; Lu, Ying-Yuan; Wang, Xin; Ren, Hong; Li, Qiang; Wang, Shu-Mei; Ding, Yu; Lou, Ya-Qing; Zhang, Guo-Liang.
Afiliação
  • Cheng HX; Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
  • Lu YY; Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
  • Wang X; Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
  • Ren H; Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
  • Li Q; Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
  • Wang SM; Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
  • Ding Y; Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
  • Lou YQ; Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China.
  • Zhang GL; Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China. Electronic address: ZhangGL168@bjmu.edu.cn.
Eur J Pharm Sci ; 123: 241-248, 2018 Oct 15.
Article em En | MEDLINE | ID: mdl-30010032
The compound 3,4­dichlorophenyl­propenoyl­sec.­butylamine (3,4­DCPB) is an antiepileptic drug. The purpose of the present research was to identify cytochrome P450 (CYP450) responsible for the metabolism of 3,4­DCPB and evaluate the effects of 3,4­DCPB on the activities of CYP450 enzymes. 3,4­DCPB was incubated with rat liver microsomes (RLMs) plus six CYP450 enzyme-specific inhibitors, or six recombinant human CYP450 enzymes (rhCYP450s). The concentrations of 3,4­DCPB and six CYP450 enzyme-activities probe drugs were detected by high-performance liquid chromatographic (HPLC). The results showed that the prototype of 3,4­DCPB was metabolized by multiple CYP450 enzymes into three metabolites, and the predominant isoforms were CYP2D6 (metabolite M1), CYP1A2 (M2), CYP2C19 and CYP3A4 (M3), respectively., in the presence of ß-NADPH (1 mM) in RLMs or rhCYP450s. Compared with the control (PB-), phenobarbital pre-treatment (PB+) significantly enhanced levels (all of p < 0.01) of hydroxylmethytobutamide (CYP2C9), 4­hydroxy­mephenytoin (CYP2C19), acetaminophen (CYP1A2), 6­hydroxychlorzoxazone (CYP2E1) and oxidized nifedipine (CYP3A4), respectively, in spite of dextrophan (CYP2D6) was not markedly enhanced in RLMs. Conversely, the inhibitory ratios of 3,4­DCPB (16 µg/mL, 59 µM) on the activities of CYP2C9, CYP2C19, CYP1A2 and CYP2D6 were 97.6%, 59.0%, 53.5% and 36.5%, respectively. However, CYP2E1 (both of PB- and PB+) and CYP3A4 (PB+) were not inhibited by 3,4­DCPB in RLMs. In conclusion, the present study showed that 3,4­DCPB was metabolized by multiple CYP450 enzymes. 3,4­DCPB inhibited the activities of CYP2C9, CYP2C19, CYP1A2 and CYP2D6, rather than that CYP2E1 and CYP3A4 enzymes, suggesting that the different effects of 3,4­DCPB on the CYP450 enzymes might influence metabolic drug-drug interaction in antiepileptics therapy.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Butilaminas / Microssomos Hepáticos / Sistema Enzimático do Citocromo P-450 / Fígado / Anticonvulsivantes Limite: Animals / Humans / Male Idioma: En Revista: Eur J Pharm Sci Assunto da revista: FARMACIA / FARMACOLOGIA / QUIMICA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Butilaminas / Microssomos Hepáticos / Sistema Enzimático do Citocromo P-450 / Fígado / Anticonvulsivantes Limite: Animals / Humans / Male Idioma: En Revista: Eur J Pharm Sci Assunto da revista: FARMACIA / FARMACOLOGIA / QUIMICA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: China