美沙酮代谢和levo-alpha-acetylmethadol (LAAM)由人类肠道细胞色素P450 3 a4 (CYP3A4):肠道代谢的潜在贡献presystemic间隙和bioactivation。

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Oda Y, Kharasch ED

美沙酮代谢和levo-alpha-acetylmethadol (LAAM)由人类肠道细胞色素P450 3 a4 (CYP3A4):肠道代谢的潜在贡献presystemic间隙和bioactivation。

J Exp其他杂志》2001年9月,298 (3):1021 - 32。

PubMed ID

11504799 (在PubMed

]

文摘

美沙酮和levo-alpha-acetylmethadol (LAAM)是阿片受体激动剂用于止痛和防止鸦片撤军。美沙酮是不活跃的代谢物2-ethylidene-1 N-demethylated顺序,5-dimethyl-3, 3-diphenylpyrrolidine (EDDP)和2-ethyl-5-methyl-3 3-diphenylpyraline(电势差)。LAAM本质上是一种前体药物,通过顺序去经历bioactivation levo-alpha-acetyl-N-normethadol (nor-LAAM)和levo-alpha-acetyl-N N-dinormethadol (dinor-LAAM)。美沙酮和LAAM由CYP3A4代谢在人类肝脏。因为它们的口服药物,CYP3A4表达在人类肠道中,我们测试了假设人类肠可以对美沙酮的代谢和LAAM,和评估CYP3A4的参与。肠微粒体美沙酮去表现出夸张的非合作的动力学和两相的Eadie-Hofstee情节。使用dual-enzyme Michaelis-Menten模型中,K (m)值是11和1200 microM EDDP 23和930 microM电势差的形成,分别。CYP3A4抑制剂(troleandomycin和酮康唑)抑制EDDP和电势差的形成> 70%。美沙酮CYP3A4的去显示两相的Eadie-Hofstee情节没有积极协调的证据;K (m)值是10和1100 microM EDDP 20和1000 microM电势差的形成。 Intestinal microsomal LAAM and nor-LAAM N-demethylation also exhibited hyperbolic kinetics and biphasic Eadie-Hofstee plots. K(m) values were 21 and 980 microM for nor-LAAM from LAAM and 18 and 1200 microM for dinor-LAAM from nor-LAAM. Troleandomycin and ketoconazole inhibited N-demethylation by >70%. LAAM and nor-LAAM metabolism by CYP3A4 showed biphasic Eadie-Hofstee plots without evidence of positive cooperativity; K(m) values were 8 and 1300 microM, 6 and 950 microM, respectively. Predicted in vivo intestinal extraction of methadone and LAAM is 21 and 33%, respectively. We conclude that methadone, LAAM, and nor-LAAM are metabolized by human intestinal microsomes; CYP3A4 is the predominant cytochrome P450 isoform; CYP3A4-catalyzed methadone, LAAM, and nor-LAAM metabolism is characterized by noncooperative, multisite kinetics; and intestinal metabolism may contribute to presystemic methadone inactivation and LAAM bioactivation.

DrugBank数据引用了这篇文章

药物酶

药物	酶	类	生物	药理作用	行动
Levacetylmethadol	细胞色素P450 3 a4	蛋白质	人类	未知的	底物	细节