CYP450 phenotyping and accurate mass identification of metabolites of the 8-aminoquinoline, anti-malarial drug primaquine.
CYP450 phenotyping and accurate mass identification of metabolites of the 8-aminoquinoline, anti-malarial drug primaquine.
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DOI：
10.1186/1475-2875-11-259
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发表时间：
2012-08-02
期刊：
影响因子：
3
通讯作者：
Melendez V
中科院分区：
文献类型：
--
作者：
Pybus BS;Sousa JC;Jin X;Ferguson JA;Christian RE;Barnhart R;Vuong C;Sciotti RJ;Reichard GA;Kozar MP;Walker LA;Ohrt C;Melendez V
8-氨基喹啉（8AQ）药物伯氨喹（PQ）是目前唯一批准的有效对抗间日疟原虫和卵形疟原虫形成株的持续肝期以及恶性疟原虫的V期配子体的药物。迄今为止，几个研究小组已经研究了在8AQ类中观察到的毒性，但是，尚未完全了解PQ血液毒性和抗疟疾特性的确切机制和/或代谢物质。在本研究中，使用细胞色素P450（CYP）和单胺氧化酶（MAO）家族的体外重组代谢酶评价PQ的代谢。基于该信息，使用标称和准确质量测量值进行代谢物鉴别实验。相对活性因子（RAF）加权固有清除率值显示，每种酶的相对作用为MAO-A、2C 19、3A 4和2D 6，对PQ代谢的贡献分别为76.1%、17.0%、5.2%和1.7%。研究表明，MAO 2D 6至少产生六种不同的氧化代谢物沿着去甲基化，而MAO-A产物来源于PQ醛（羧基PQ的前体）。CYP 2C 19和3A 4仅产生痕量水平的羟基化物质。作为这项工作的结果，已将β 2D 6和MAO-A作为与PQ代谢相关的关键酶，并且先前确定为可能在疗效和溶血毒性中发挥作用的代谢物已归因于通过β 2D 6介导的途径产生。
The 8-aminoquinoline (8AQ) drug primaquine (PQ) is currently the only approved drug effective against the persistent liver stage of the hypnozoite forming strains Plasmodium vivax and Plasmodium ovale as well as Stage V gametocytes of Plasmodium falciparum. To date, several groups have investigated the toxicity observed in the 8AQ class, however, exact mechanisms and/or metabolic species responsible for PQ’s haemotoxic and anti-malarial properties are not fully understood. In the present study, the metabolism of PQ was evaluated using in vitro recombinant metabolic enzymes from the cytochrome P450 (CYP) and mono-amine oxidase (MAO) families. Based on this information, metabolite identification experiments were performed using nominal and accurate mass measurements. Relative activity factor (RAF)-weighted intrinsic clearance values show the relative role of each enzyme to be MAO-A, 2C19, 3A4, and 2D6, with 76.1, 17.0, 5.2, and 1.7% contributions to PQ metabolism, respectively. CYP 2D6 was shown to produce at least six different oxidative metabolites along with demethylations, while MAO-A products derived from the PQ aldehyde, a pre-cursor to carboxy PQ. CYPs 2C19 and 3A4 produced only trace levels of hydroxylated species. As a result of this work, CYP 2D6 and MAO-A have been implicated as the key enzymes associated with PQ metabolism, and metabolites previously identified as potentially playing a role in efficacy and haemolytic toxicity have been attributed to production via CYP 2D6 mediated pathways.
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影响因子：
3.8
作者：
Ganesan, Shobana;Tekwani, Babu L.;Walker, Larry A.
通讯作者：
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影响因子：
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作者：
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DOI：
10.1111/j.1365-2125.1985.tb02709.x
发表时间：
1985-01-01
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作者：
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作者：
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作者：
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