抑制CYP3A4和CYP3A5催化阿普唑仑和奎宁的代谢酮康唑作为外消旋体和四种不同的对映体。

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Allqvist A, Miura J, Bertilsson L, Mirghani RA

抑制CYP3A4和CYP3A5催化阿普唑仑和奎宁的代谢酮康唑作为外消旋体和四种不同的对映体。

《欧洲临床药物学杂志》2007年2月;63(2):173-9。doi: 10.1007 / s00228 - 006 - 0230 - z。Epub 2007年1月3日

PubMed ID

17200836 (PubMed视图

］

摘要

目的:抗真菌药物酮康唑(KTZ)被认为是一种抑制剂，特别是CYP3A亚家族的抑制剂，它催化多种药物的代谢。KTZ与CYP3A底物之间的相互作用在体内和体外均有报道。但大多数都涉及KTZ外消旋体。KTZ外消旋体和单独的对映体2R,4R;2 r, 4 s;2S,4S，和2S,4R对抑制阿普唑仑和奎宁代谢的选择性进行了评估。方法:在重组CYP3A4和CYP3A5的人肝微粒体(HLM)体外体系中研究阿普唑仑和奎宁代谢的抑制作用。用HPLC和LC-MS分别测定了形成的3-羟基奎宁和4-和-羟基阿普唑仑的浓度。结果:CYP3A4和CYP3A5对奎宁3-羟基化有相似程度的催化作用。对每个HLM、CYP3A4和CYP3A5, 4-羟阿普唑仑的形成率均高于α -羟阿普唑仑。 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.

引用本文的药物库数据

药物酶

药物	酶	种类	生物	药理作用	行动
阿普唑仑	细胞色素P450 3A5	蛋白质	人类	未知的	底物	细节
酮康唑	细胞色素P450 3A5	蛋白质	人类	没有	抑制剂	细节
奎宁	细胞色素P450 3A4	蛋白质	人类	未知的	底物 抑制剂 诱导物	细节