Interaction between 3,4dichlorophenylpropenoylsec.butylamine (3,4DCPB), an antiepileptic drug, and cytochrome P450 in rat liver microsomes and recombinant human enzymes in vitro.
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 (1â¯mM) in RLMs or rhCYP450s. Compared with the control (PB-), phenobarbital pre-treatment (PB+) significantly enhanced levels (all of pâ¯<â¯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⯵g/mL, 59⯵M) 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Butilaminas
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Microssomos Hepáticos
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Sistema Enzimático do Citocromo P-450
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Fígado
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Anticonvulsivantes
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Eur J Pharm Sci
Assunto da revista:
FARMACIA
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FARMACOLOGIA
/
QUIMICA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
China