Reductive Metabolism Influences the Toxicity and Pharmacokinetics of the Hypoxia-Targeted Benzotriazine Di-Oxide Anticancer Agent SN30000 in Mice.
Reductive Metabolism Influences the Toxicity and Pharmacokinetics of the Hypoxia-Targeted Benzotriazine Di-Oxide Anticancer Agent SN30000 in Mice.
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DOI：
10.3389/fphar.2017.00531
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发表时间：
2017
影响因子：
5.6
通讯作者：
Hicks KO
中科院分区：
文献类型：
--
作者：
Gu Y;Chang TT;Wang J;Jaiswal JK;Edwards D;Downes NJ;Liyanage HDS;Lynch CRH;Pruijn FB;Hickey AJR;Hay MP;Wilson WR;Hicks KO
3-(3-Morpholinopropyl)-7，8-dihydro-6H-indeno[5，6-e][1，2，4]triazine 1，4-二氧化物(SN30-000)是一种研究得很好的生物还原前体药物替拉帕明的类似物，它可以提高抗肿瘤移植瘤中缺氧细胞的活性。然而，人们对其在正常组织中的生物转化知之甚少。在这里，我们评估SN30000的生物转化对其在NIH-III小鼠中的毒代动力学的影响。代谢产物表现为还原为1-N-氧化物(M14)，吗啉侧链(主要是烷酸M18)和生色团的氧化，以及随后的葡萄糖醛酸化。HT29肿瘤移植瘤的存在不影响SN30000及其还原代谢物的血浆药代动力学，表明正常组织中广泛减少。这种生物还原代谢，正如肝脏S9制剂所模拟的那样，被氧气强烈抑制，表明它是通过单电子(自由基)中间体进行的，此前SN30000曾参与诱导DNA双链断裂和细胞毒性。SN30000和M14(而不是M18)的血浆药代动力学与可逆性急性临床症状(活动性降低)和明显低温(最大耐受量后直肠温度下降∼8°C)的时间密切相关。尽管M14不能引起SN30000所致的肾和肺组织病理学改变，但给予TPZ或M14也可引起类似的急性毒性。在低氧细胞培养中，M14也缺乏抗增殖能力。此外，在有氧培养中，M14表现出比SN30000慢得多的氧化还原循环。因此，通过M14介导的非生物还原机制似乎是SN30000急性毒性的原因，而晚期毒性与其单电子还原导致的DNA损伤是一致的。SN30000在小鼠体内的非线性pk符合二室药动学模型，该模型通过依赖温度的生物还原代谢来确定SN30000对M14的清除。这项研究证明了非肿瘤生物还原代谢在以肿瘤缺氧为靶点的苯并三氮二氧化物的毒理学和药代动力学中的重要性。
3-(3-Morpholinopropyl)-7,8-dihydro-6H-indeno[5,6-e][1,2,4]triazine 1,4-dioxide (SN30- 000), an analog of the well-studied bioreductive prodrug tirapazamine (TPZ), has improved activity against hypoxic cells in tumor xenografts. However, little is known about its biotransformation in normal tissues. Here, we evaluate implications of biotransformation of SN30000 for its toxicokinetics in NIH-III mice. The metabolite profile demonstrated reduction to the 1-N-oxide (M14), oxidation of the morpholine side-chain (predominantly to the alkanoic acid M18) and chromophore, and subsequent glucuronidation. Plasma pharmacokinetics of SN30000 and its reduced metabolites was unaffected by the presence of HT29 tumor xenografts, indicating extensive reduction in normal tissues. This bioreductive metabolism, as modeled by hepatic S9 preparations, was strongly inhibited by oxygen indicating that it proceeds via the one-electron (radical) intermediate previously implicated in induction of DNA double strand breaks and cytotoxicity by SN30000. Plasma pharmacokinetics of SN30000 and M14 (but not M18) corresponded closely to the timing of reversible acute clinical signs (reduced mobility) and marked hypothermia (rectal temperature drop of ∼8°C at nadir following the maximum tolerated dose). Similar acute toxicity was elicited by dosing with TPZ or M14, although M14 did not induce the kidney and lung histopathology caused by SN30000. M14 also lacked antiproliferative potency in hypoxic cell cultures. In addition M14 showed much slower redox cycling than SN30000 in oxic cultures. Thus a non-bioreductive mechanism, mediated through M14, appears to be responsible for the acute toxicity of SN30000 while late toxicities are consistent with DNA damage resulting from its one-electron reduction. A two-compartment pharmacokinetic model, in which clearance of SN30000 is determined by temperature-dependent bioreductive metabolism to M14, was shown to describe the non-linear PK of SN30000 in mice. This study demonstrates the importance of non-tumor bioreductive metabolism in the toxicology and pharmacokinetics of benzotriazine di-oxides designed to target tumor hypoxia.
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影响因子：
2.6
作者：
Beppu T;Sasaki T;Terasaki K;Saura H;Mtsuura H;Ogasawara K;Sasaki M;Ehara S;Iwata R;Takai Y
通讯作者：
Takai Y
影响因子：
3
作者：
Gu, Yongchuan;Guise, Christopher P.;Wilson, William R.
通讯作者：
Wilson, William R.
影响因子：
5.8
作者：
Elwell, JH;Siim, BG;Brown, JM
通讯作者：
Brown, JM
影响因子：
10.3
作者：
Hicks, Kevin O.;Pruijn, Frederik B.;Wilson, William R.
通讯作者：
Wilson, William R.
影响因子：
3.9
作者：
Gu, Yongchuan;Atwell, Graham J.;Wilson, William R.
通讯作者：
Wilson, William R.