The metabolism of primaquine to its active metabolite is dependent on CYP 2D6.
The metabolism of primaquine to its active metabolite is dependent on CYP 2D6.
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DOI：
10.1186/1475-2875-12-212
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发表时间：
2013-06-20
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;Marcsisin SR;Jin X;Deye G;Sousa JC;Li Q;Caridha D;Zeng Q;Reichard GA;Ockenhouse C;Bennett J;Walker LA;Ohrt C;Melendez V
8-氨基喹啉(8AQ)类药物伯氨喹(PQ)的疗效历来与CYP介导的代谢有关。尽管到目前为止，没有明确的证据表明代谢途径或特定的代谢物是活性所必需的，但最近的文献表明，CyP2D6在氧化还原活性代谢物的生成中发挥了作用。在本研究中，使用了特定的细胞色素PYP2D6抑制剂帕罗西汀来评估其对特定酚类代谢物产生的影响，这些代谢物被认为与PQ疗效有关。此外，与正常C57背景和人源化CYP 2D6小鼠比较，PQ因果预防(发展中的肝期)CYP 2D基因敲除小鼠对伯氏疟原虫的效果进行了评估，以确定CYP 2D6代谢对PQ活性的直接影响。在CYP 2D基因敲除小鼠中，PQ在20或40 mg/kg时没有活性，而在正常小鼠中，PQ在20 mg/kg时显示出5/5的活性。在人源化的CYP 2D6小鼠中，部分恢复了对发育中的肝脏阶段的活性。这些结果明确地表明，PQ在CYP 2D6中的代谢对于抗疟疾因果预防的有效性是必不可少的。
The efficacy of the 8-aminoquinoline (8AQ) drug primaquine (PQ) has been historically linked to CYP-mediated metabolism. Although to date no clear evidence exists in the literature that unambiguously assigns the metabolic pathway or specific metabolites necessary for activity, recent literature suggests a role for CYP 2D6 in the generation of redox active metabolites. In the present study, the specific CYP 2D6 inhibitor paroxetine was used to assess its effects on the production of specific phenolic metabolites thought to be involved in PQ efficacy. Further, PQ causal prophylactic (developing liver stage) efficacy against Plasmodium berghei in CYP 2D knockout mice was assessed in comparison with a normal C57 background and with humanized CYP 2D6 mice to determine the direct effects of CYP 2D6 metabolism on PQ activity. PQ exhibited no activity at 20 or 40 mg/kg in CYP 2D knockout mice, compared to 5/5 cures in normal mice at 20 mg/kg. The activity against developing liver stages was partially restored in humanized CYP 2D6 mice. These results unambiguously demonstrate that metabolism of PQ by CYP 2D6 is essential for anti-malarial causal prophylaxis efficacy.
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影响因子：
3.8
作者：
Ganesan, Shobana;Tekwani, Babu L.;Walker, Larry A.
通讯作者：
Walker, Larry A.
影响因子：
5.9
作者：
Yu, AM;Idle, JR;Gonzalez, FJ
通讯作者：
Gonzalez, FJ
DOI：
10.1124/jpet.105.090407
发表时间：
2005-12-01
影响因子：
3.5
作者：
Bowman, ZS;Jollow, DJ;McMillan, DC
通讯作者：
McMillan, DC
影响因子：
3
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
通讯作者：
Melendez V
DOI：
10.1124/jpet.102.041459
发表时间：
2002-12-01
影响因子：
3.5
作者：
Bolchoz, LJC;Gelasco, AK;McMillan, DC
通讯作者：
McMillan, DC