Comparative in vitro metabolism of phospho-tyrosol-indomethacin by mice, rats and humans.
Comparative in vitro metabolism of phospho-tyrosol-indomethacin by mice, rats and humans.
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DOI：
10.1016/j.bcp.2013.01.031
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发表时间：
2013-04-15
影响因子：
5.8
通讯作者：
Rigas, Basil
中科院分区：
文献类型：
--
作者：
Xie, Gang;Zhou, Dingying;Cheng, Ka-Wing;Wong, Chi C.;Rigas, Basil
磷酸酪醇吲哚美辛（Phospho-tyrosol-indomethacin，PTI; MPI 621）是一种新型的抗肿瘤药物，比传统的吲哚美辛更有效、更安全。在这里，我们表明，PTI在体外和体内被广泛代谢。在肝微粒体和大鼠体内，PTI被羧酸酯酶快速水解生成吲哚美辛。PTI还经历细胞色素P450（CYP 1A 1）介导的酪醇部分的羟基化和吲哚美辛部分的O-去甲基化。在五种主要的人类CYP中，CYP 3A 4和CYP 2D 6分别催化PTI的羟基化和O-去甲基化反应;而CYP 1A 2、2C 9和2C 19对PTI无活性。与PTI相反，吲哚美辛主要通过CYP 2C 9进行O-脱甲基化，CYP 2C 9更喜欢酸性底物。PTI的水解和O-脱甲基代谢产物进一步葡萄糖醛酸化和硫酸化，促进药物消除和解毒。我们观察到PTI代谢率的物种间差异。在不同种属的肝微粒体中，PTI分别在小鼠、人和大鼠肝微粒体中水解、羟基化和O-脱甲基化最快。这些结果反映了这些物种之间的羧酸酯酶和酯酶同工酶的差异表达模式。在来自各种组织的人微粒体中，PTI在肝和肠微粒体中比在肾和肺微粒体中经历更快的羧酸酯酶和CYP催化反应。总之，我们的研究结果建立了PTI的代谢途径，揭示了其代谢的显著种间差异，并提供了对潜在生化机制的见解。
Phospho-tyrosol-indomethacin (PTI; MPI 621), a novel anti-cancer agent, is more potent and safer than conventional indomethacin. Here, we show that PTI was extensively metabolized in vitro and in vivo. PTI was rapidly hydrolyzed by carboxylesterases to generate indomethacin as its major metabolite in the liver microsomes and rats. PTI additionally undergoes cytochromes P450 (CYP)-mediated hydroxylation at its tyrosol moiety and O-demethylation at its indomethacin moiety. Of the five major human CYPs, CYP3A4 and CYP2D6 catalyze the hydroxylation and O-demethylation reactions of PTI, respectively; whereas CYP1A2, 2C9 and 2C19 are inactive towards PTI. In contrast to PTI, indomethacin is primarily O-demethylated by CYP2C9, which prefers acidic substrates. The hydrolyzed and O-demethylated metabolites of PTI are further glucuronidated and sulfated, facilitating drug elimination and detoxification. We observed substantial inter-species differences in the metabolic rates of PTI. Among the liver microsomes from various species, PTI was the most rapidly hydrolyzed, hydroxylated and O-demethylated in mouse, human and rat liver microsomes, respectively. These results reflect the differential expression patterns of carboxylesterase and CYP isoforms among these species. Of the human microsomes from various tissues, PTI underwent more rapid carboxylesterase-and CYP-catalyzed reactions in liver and intestine microsomes than in kidney and lung microsomes. Together, our results establish the metabolic pathways of PTI, reveal significant inter-species differences in its metabolism, and provide insights into the underlying biochemical mechanisms.
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影响因子：
4.8
作者：
Ackerstaff, Ellen;Gimi, Barjor;Bhujwalla, Zaver M.
通讯作者：
Bhujwalla, Zaver M.
影响因子：
3.7
作者：
Shiff, SJ;Koutsos, MI;Rigas, B
通讯作者：
Rigas, B
影响因子：
5
作者：
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通讯作者：
BEAVEN, MA
影响因子：
2.1
作者：
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通讯作者：
Naito, Shinsaku
影响因子：
3.9
作者：
Kapelyukh, Yury;Paine, Mark J. I.;Roberts, Gordon C. K.
通讯作者：
Roberts, Gordon C. K.