Pharmacokinetics and metabolism of the prodrug DB289 (2,5-bis[4-(N-methoxyamidino)phenyl]furan monomaleate) in rat and monkey and its conversion to the antiprotozoal/antifungal drug DB75 (2,5-bis(4-guanylphenyl)furan dihydrochloride)
Pharmacokinetics and metabolism of the prodrug DB289 (2,5-bis[4-(N-methoxyamidino)phenyl]furan monomaleate) in rat and monkey and its conversion to the antiprotozoal/antifungal drug DB75 (2,5-bis(4-guanylphenyl)furan dihydrochloride)
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DOI：
10.1124/dmd.106.013391
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发表时间：
2007-06-01
影响因子：
3.9
通讯作者：
Trendler, Kerri L.
中科院分区：
文献类型：
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作者：
Midgley, Ian;Fitzpatrick, Karen;Trendler, Kerri L.
DB289（马来酸帕夫脒；2,5-二[4-（n -甲氧基氨基）苯基]呋喃单马来酸酯）是DB75（盐酸呋喃脒；2,5-二（4-鸟酰苯基）呋喃二盐酸盐）的前药，DB75是一种与喷他脒相关的芳香适应症，已证明对非洲锥虫病、卡氏肺孢子虫肺炎和疟疾有良好的疗效，但缺乏足够的口服有效性。研究了C-14- DB289口服和静脉给药后在大鼠和猴体内的药代动力学和代谢。口服剂量在两种物种中吸收良好（类似于50-70%）并有效转化为DB75，但受首过代谢和肝脏滞留的影响，将其全身生物利用度限制在10%至20%。DB289的清除接近肝脏血浆流量，其大体积分布与广泛的组织结合一致。DB289在四种动物和人的血浆蛋白结合率为97 ~ 99%，而DB75的结合率明显较低，且具有物种和浓度依赖性。前药和活性代谢物加起来占口服剂量后血浆放射性的不到20%，但DB75是脑和肝脏等关键器官的主要放射化学成分，并且在很大程度上负责体内C-14的持续存在。放射性的主要排泄途径是通过粪便，尽管胆道分泌不是特别广泛。高效液相色谱和液相色谱-质谱分析表明，DB75的形成涉及到两个n -甲氧基的连续损失，或者直接损失，或者通过o -去甲基化，然后将生成的肟还原为脒。据估计，大鼠口服DB289的近一半和猴子口服DB289的约三分之一被代谢为DB75。
DB289 (pafuramidine maleate; 2,5-bis[4-(N-methoxyamidino)phenyl] furan monomaleate) is a prodrug of DB75 (furamidine dihydrochloride; 2,5-bis(4- guanylphenyl)furan dihydrochloride), an aromatic dication related to pentamidine that has demonstrated good efficacy against African trypanosomiasis, Pneumocystis carinii pneumonia, and malaria, but lacks adequate oral availability. The pharmacokinetics and metabolism of C-14- DB289 have been investigated in rat and monkey after oral and intravenous administration. Oral doses were well absorbed (similar to 50-70%) and effectively converted to DB75 in both species but subject to first-pass metabolism and hepatic retention, limiting its systemic bioavailability to 10 to 20%. Clearance of DB289 approximated the liver plasma flow and its large volume of distribution was consistent with extensive tissue binding. Plasma protein binding of DB289 was 97 to 99% in four animal species and humans, but that of DB75 was noticeably less and more species- and concentration-dependent. Together, prodrug and active metabolite accounted for less than 20% of the plasma radioactivity after an oral dose, but DB75 was the major radiochemical component in key organs such as brain and liver and was largely responsible for the persistence of C-14 in the body. The predominant route of excretion of radioactivity was via the feces, although biliary secretion was not particularly extensive. High- performance liquid chromatography and liquid chromatography-mass spectrometry investigations showed that the formation of DB75 from the prodrug involved the sequential loss of the two N-methoxy groups, either directly or by O-demethylation followed by reduction of the resulting oxime to the amidine. It was estimated that almost half of an oral dose of DB289 to rats and about one-third of that to monkeys was metabolized to DB75.