Halofantrine在微粒体代谢男:主要角色的CYP 3 a4和a5 CYP 3。

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Baune B, Flinois JP,可•福尔兰正V, Gimenez F, Taburet, Becquemont L, Farinotti R

Halofantrine在微粒体代谢男:主要角色的CYP 3 a4和a5 CYP 3。

51 J制药药物杂志。1999年4月;(4):419 - 26所示。

PubMed ID

10385214 (在PubMed

]

文摘

我们已经阐明的贡献不同的酶参与N-debutylation halofantrine在人肝微粒体。酮康唑的影响以及细胞色素P450 (CYP) 3对halofantrine基质代谢也被研究过。抗疟药halofantrine被代谢成一个主要代谢物,N-debutylhalofantrine。从九个肝脏微粒体从人,N-debutylation halofantrine高度变量明显Michaelis-Menten常数K V (max)和(m)的值215 + -172 pmol /分钟(1)毫克(1)和48 + / -26 micromol L(1),分别(平均+ /标准偏差)。N-debutylhalofantrine的形成是细胞色素P450 (CYP)介导的。研究使用的选择性抑制剂个人CYP透露CYP 3的角色如N-debutylhalofantrine的形成。alpha-Naphthoflavone CYP 3激活,增加代谢产物的形成。从12肝微粒体从人的速度N-debutylation halofantrine相关强烈CYP 3 a4相对水平(P = 0.002)和更少的强劲,但值得注意的是,CYP 2 c8水平(P = 0.025)。进一步描述CYP-mediated halofantrine代谢,孵化项目被用酵母进行微粒体表达特定CYP 3 a4, CYP 3 a5, CYP 2 d6, CYP 2 c8和CYP 2 c19从人。N-debutylhalofantrine六岁的生成速率和十二倍的CYP 3 a4比CYP 3 a5和CYP 2 c8,分别。 CYP 2D6 and CYP 2C19 did not mediate the N-debutylation of halofantrine, but, because in-vivo CYP 2C8 is present at lower concentrations than CYP 3A in the liver in man, the involvement of CYP 3As would be predominant. Diltiazem, erythromycin, nifedipine and cyclosporin (CYP 3A substrates) inhibited halofantrine metabolism. Similarly, ketoconazole inhibited, non-competitively, formation of N-debutylhalofantrine with an inhibition constant, K(i), of 0.05 microM. The theoretical percentage inhibition of halofantrine metabolism in-vivo by ketoconazole was estimated to be 99%. These results indicate that both CYP 3A4 and CYP 3A5 metabolize halofantrine, with major involvement of CYP 3A4. In-vivo, the other CYPs have a minor role only. Moreover, strong inhibition, and consequently increased halofantrine cardiotoxicity, might occur with the association of ketoconazole or other CYP 3A4 substrates.

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药物酶

药物	酶	类	生物	药理作用	行动
Halofantrine	细胞色素P450 2 c8	蛋白质	人类	未知的	底物	细节
Halofantrine	细胞色素P450 3 a4	蛋白质	人类	未知的	底物	细节
Halofantrine	细胞色素P450 3 a5	蛋白质	人类	未知的	底物	细节