抑制CYP3A4和CYP3A5催化代谢阿普唑仑和奎宁的酮康唑外消旋体和四个不同的对映体。

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Allqvist,三浦J,解决L Mirghani RA

抑制CYP3A4和CYP3A5催化代谢阿普唑仑和奎宁的酮康唑外消旋体和四个不同的对映体。

63年2月欧元中国新药杂志。2007;(2):173 - 9。doi: 10.1007 / s00228 - 006 - 0230 - z。Epub 2007年1月3。

PubMed ID

17200836 (在PubMed

]

文摘

目的:抗真菌药物酮康唑(KTZ)是已知的抑制剂,特别是CYP3A亚科,催化多种药物的代谢。KTZ和CYP3A基质之间的相互作用在体内和体外都已报告。然而,他们中的大多数涉及KTZ外消旋体。KTZ外消旋体的分离对映体,2 r, 4 r;2 r, 4 s;2 s, 4 s, 2 s, 4 r,评估他们的选择性抑制阿普唑仑和奎宁的新陈代谢。方法:阿普唑仑和奎宁的抑制体外代谢研究是一个系统的人类肝脏微粒体(高),重组CYP3A4和CYP3A5。形成的浓度3-hydroxyquinine 4 -和用高效液相色谱检测alpha-hydroxyalprazolam质。结果:奎宁3-hydroxylation被CYP3A4催化相似程度和CYP3A5。4-hydroxyalprazolam的形成率高于alpha-hydroxyalprazolam对于每个问题,CYP3A4和CYP3A5。 KTZ racemate and enantiomers showed differential inhibitory effects of quinine and alprazolam metabolism. Quinine metabolism catalyzed by HLM, CYP3A4 and CYP3A5 was potently inhibited by the trans-enantiomer KTZ 2S,4S, with IC(50) value of 0.16 microM for HLM, 0.04 microM for CYP3A4 and 0.11 microM for CYP3A5. The same enantiomer showed the lowest IC(50) values of 0.11 microM for HLM and 0.04 microM for CYP3A5 with respect to alprazoalm 4-hydroxylation and also the same pattern for alprazolamalpha-hydroxylation, 0.13 microM for HLM and 0.05 microM for CYP3A5. Alprazolam metabolism (both alpha- and 4- hydroxylations) catalyzed by CYP3A4 was inhibited potently by the cis-enantiomer KTZ 2S,4R, with IC(50) values of 0.03 microM. CONCLUSIONS: Alprazolam and quinine metabolism is catalyzed by both CYP3A4 and CYP3A5. The present study showed that different KTZ enantiomers inhibit CYP3A4 and CYP3A5 to different degrees, indicating that structural differences among the enantiomers would be related to their inhibitory potency on these two enzymes.

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药物酶

药物	酶	类	生物	药理作用	行动
阿普唑仑	细胞色素P450 3 a5	蛋白质	人类	未知的	底物	细节
酮康唑	细胞色素P450 3 a5	蛋白质	人类	没有	抑制剂	细节
奎宁	细胞色素P450 3 a4	蛋白质	人类	未知的	底物 抑制剂 诱导物	细节