Quantification of In Vivo Metabolic Activity of CYP2D6 Genotypes and Alleles Through Population Pharmacokinetic Analysis of Vortioxetine.
Quantification of In Vivo Metabolic Activity of CYP2D6 Genotypes and Alleles Through Population Pharmacokinetic Analysis of Vortioxetine.
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DOI：
10.1002/cpt.1972
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发表时间：
2021-01
影响因子：
6.7
通讯作者：
Brøsen K
中科院分区：
文献类型：
--
作者：
Frederiksen T;Areberg J;Schmidt E;Bjerregaard Stage T;Brøsen K
从基因型数据分配CYP 2D 6表型可能具有挑战性，尽管努力使翻译标准化，但目前还没有普遍接受的方法。为了便于标准化，仍然需要精确地定量不同CYP 2D 6基因型的体内功能。沃替西汀主要通过CYP 2D 6代谢为主要代谢产物Lu AA 34443。本研究的目的是通过沃替西汀和Lu AA 34443的群体药代动力学（PopPK）建模来量化不同CYP 2D 6等位基因和基因型的体内CYP 2D 6活性。汇总了来自29项临床药理学研究的1，140例受试者的沃替西汀和Lu AA 34443血浆浓度数据，用于分析。联合PopPK模型同时描述了沃替西汀和Lu AA 34443的药代动力学，并提供了每例受试者的CYP 2D 6介导的代谢估计值。正常分类为CYP 2D 6中间代谢者（IM）的受试者表现出不同水平的CYP 2D 6活性，与两个功能降低等位基因的携带者相比，一个功能完全等位基因和一个功能无效等位基因的携带者的CYP 2D 6活性高77%（P < 0.0001）。功能降低的等位基因与不同程度的CYP 2D 6活性降低有关。将全功能等位基因的活性固定为1.0，CYP 2D 6 *9、CYP 2D 6 *10、CYP 2D 6 *17和CYP 2D 6 *41的相对活性分别为0.22、0.37、0.17和0.21。CYP 2D 6 *10活性显著高于CYP 2D 6 *17（P = 0.01）和CYP 2D 6 *41（P = 0.02）。这些结果需要进一步讨论当前的CYP 2D 6基因型-表型分类系统，特别是关于功能降低的等位基因和IM表型。
Assignment of CYP2D6 phenotype from genotype data can be challenging and despite efforts to standardize translation, there is currently no universally accepted method. To facilitate standardization, there remains a need to precisely quantify the in vivo function of different CYP2D6 genotypes. Vortioxetine is metabolized to its major metabolite, Lu AA34443, primarily via CYP2D6. The aim of this study was to quantify the in vivo CYP2D6 activity of different CYP2D6 alleles and genotypes through population pharmacokinetic (PopPK) modeling of vortioxetine and Lu AA34443. Plasma concentration data of vortioxetine and Lu AA34443 from 1,140 subjects originating from 29 clinical pharmacology studies were pooled for the analysis. A joint PopPK model described the pharmacokinetics of vortioxetine and Lu AA34443 simultaneously and provided estimates of the CYP2D6‐mediated metabolism for each subject. Subjects normally classified as CYP2D6 intermediate metabolizers (IMs) showed different levels of CYP2D6 activity with carriers of one fully functional allele and one null function allele having 77% higher CYP2D6 activity compared with carriers of two decreased function alleles (P < 0.0001). The decreased function alleles were associated with different levels of reduction of CYP2D6 activity. Fixing the activity of fully functional alleles to 1.0, the relative activities of CYP2D6*9, CYP2D6*10, CYP2D6*17, and CYP2D6*41 were 0.22, 0.37, 0.17, and 0.21, respectively. The activity of CYP2D6*10 was shown to be significantly greater than that of CYP2D6*17 (P = 0.01) and CYP2D6*41 (P = 0.02). These results warrant further discussion of current CYP2D6 genotype‐phenotype classification systems particularly regarding decreased function alleles and the IM phenotype.
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影响因子：
3.2
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Chen G;Lee R;Højer AM;Buchbjerg JK;Serenko M;Zhao Z
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Zhao Z
影响因子：
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Gaedigk, A.;Simon, S. D.;Leeder, J. S.
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Leeder, J. S.
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6.7
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Klein TE
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3.1
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