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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >CYP2B6 CYP2B6 *6 Genotype Specific Differences in Artemether‐Lumefantrine Disposition in Healthy Volunteers
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CYP2B6 CYP2B6 *6 Genotype Specific Differences in Artemether‐Lumefantrine Disposition in Healthy Volunteers

机译：CYP2B6 CYP2B6 * 6基因型在健康志愿者身上的蒿甲醚 - Lumefantrine处置的特异性差异

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Abstract Cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of the antimalarial drugs artemether and lumefantrine. Here we investigated the effect of CYP2B6 *6 on the plasma pharmacokinetics of artemether, lumefantrine, and their metabolites in healthy volunteers. Thirty healthy and previously genotyped adult volunteers—15 noncarriers ( CYP2B6*1/*1 ) and 15 homozygote carriers ( CYP2B6*6/*6 )—selected from a cohort of 150 subjects from the Ilorin metropolitan area were administered the complete 3‐day course of artemether and lumefantrine (80 and 480 mg twice daily, respectively). Intensive pharmacokinetic sampling was conducted at different time points before and after the last dose. Plasma concentrations of artemether, lumefantrine, dihydroartemisinin, and desbutyllumefantrine were quantified using validated liquid chromatography–mass spectrometric methods. Pharmacokinetic parameters were evaluated using noncompartmental analysis. Artemether clearance of CYP2B6*6/*6 volunteers was nonsignificantly lower by 26% (ratios of geometric mean [90% CI]; 0.74 [0.52‐1.05]), and total exposure (the area under the plasma concentration‐time curve from time 0 to infinity [AUC 0‐∞ ]) was greater by 35% (1.35 [0.95‐1.93]) when compared with those of *1/*1 volunteers. Similarly, assuming complete bioconversion from artemether, the dihydroartemisinin AUC 0‐∞ was 22% lower. On the contrary, artemether‐to‐dihydroartemisinin AUC 0‐∞ ratio was 73% significantly higher (1.73 [1.27‐2.37]). Comparison of lumefantrine exposure and lumefantrine‐to‐desbutyllumefantrine metabolic ratio of *6/*6 with corresponding data from *1/*1 volunteers showed no differences. The increased artemether‐to‐dihydroartemisinin metabolic ratio of *6/*6 volunteers is unlikely to result in differences in artemether‐lumefantrine efficacy and treatment outcomes. This is the first study in humans to associate CYP2B6*6 genotype with artemether disposition.
机译：摘要细胞色素P450 2B6（CYP2B6）参与抗疟药蒿蒿和Lumefantrine的代谢。在这里，我们研究了CYP2B6 * 6对健康志愿者血浆药代动力学的CYP2B6 * 6对健康志愿者的代谢产物的影响。从ILorin Metropolitan地区的150个受试者的队列中选择3天的三十个健康和先前基因分型的成人志愿者-15非载体（CYP2B6 * 1 / * 1）和15个纯合子载体（CYP2B6 * 6 / * 6）。野生醚和Lumefantrine的过程（分别为80和480毫克，分别为每日两次）。在最后剂量之前和之后的不同时间点进行了强化药代动力学取样。使用验证的液相色谱 - 质谱法定量了替醚，Lumefantrine，二氢氨基苷和Desbutyllumefantrine的血浆浓度。使用非组件分析评估药代动力学参数。 CYP2B6 * 6 / * 6志愿者的艺术间隙不显着降低26％（几何平均值[90％CI]; 0.74 [0.52-1.05]）和完全暴露（血浆浓度 - 时间曲线下的区域与* 1 / * 1志愿者的志愿者相比，0到Infinity [AUC 0-∞]）更大35％（1.35 [0.95-1.93]）。类似地，假设从刷籽中完成生物转化，二氢氨基蛋白AUC 0-β降低22％。相反，替醚至二氢氨基氨基AUC 0-ζ比例为73％（1.73 [1.27-2.37]）。 Lumefantrine暴露的比较和Lumefantrine-to-desfulllumefentrine代谢比例* 6 / * 6，来自* 1 / * 1志愿者的相应数据显示没有差异。增加的替醚至二氢氨基蛋白代谢比例为* 6 / * 6志愿者不太可能导致蒿甲醚 - Lumefantrine疗效和治疗结果的差异。这是人类第一次研究CYP2B6 * 6基因型与蒿甲酸的研究。

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