Fang Ping, Zheng Xiang, He Jiayang, Ge Honglei, Tang Pengfei, Cai Jianping, Hu Guoxin
Department of Pharmacology, School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang.
The Ministry of Health (MOH) Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China.
Drug Des Devel Ther. 2017 Apr 21;11:1283-1290. doi: 10.2147/DDDT.S133814. eCollection 2017.
Cytochrome P450 2D6 (CYP2D6), a member of the CYP450 enzyme super family, is a polymorphic enzyme that metabolizes ~25% of therapeutic drugs. CYP2D6 exhibits significant genetic polymorphisms which might cause adverse effects and therapeutic failures of some drugs.
The purpose of this study was to evaluate the catalytic activities of 22 novel CYP2D6 alleles (, *, *, *, *, *, *, *, *, *, *, *, , , , , , , , , , ) on the metabolism of gefitinib in vitro.
CYP2D6 variants were incubated with 1-100 μM gefitinib for 60 min at 37°C and the reaction was terminated by cooling to -80°C immediately. Gefitinib and its metabolite -desmethyl gefitinib were analyzed by an ultra-performance liquid chromatography-tandem mass spectrometry system. Compared to CYP2D6.1, most CYP2D6 variants exhibited significantly decreased relative clearance values (from 3.11% to 79.35%), whereas CYP2D6.92 and CYP2D6.96 displayed no detectable enzyme activity. Only CYP2D6.94 exhibited a markedly increased intrinsic clearance value, and eight variants (CYP2D6.88, CYP2D6.89, CYP2D6.91, CYP2D6.97, V342M, R344Q, F219S, and F164L) showed no significant difference. In addition, 23 CYP2D6 allelic isoforms exhibited substrate inhibition trend toward gefitinib.
As the first study of all the aforementioned alleles for gefitinib metabolism, these comprehensive data may help in the clinical assessment of the metabolism of gefitinib, and may also offer a reference for personalized treatment with gefitinib in clinical settings.
细胞色素P450 2D6（CYP2D6）是CYP450酶超家族的成员之一，是一种可代谢约25%治疗药物的多态性酶。CYP2D6表现出显著的基因多态性，这可能导致某些药物产生不良反应和治疗失败。
本研究旨在评估22种新型CYP2D6等位基因（，，，，，，，，，，，*，，，，，，，，，，）在体外对吉非替尼代谢的催化活性。
将CYP2D6变体与1 - 100 μM吉非替尼在37°C孵育60分钟，然后立即冷却至 - 80°C终止反应。通过超高效液相色谱 - 串联质谱系统分析吉非替尼及其代谢产物 - 去甲基吉非替尼。与CYP2D6.1相比，大多数CYP2D6变体的相对清除率值显著降低（从3.11%至79.35%），而CYP2D6.92和CYP2D6.96未显示出可检测的酶活性。仅CYP2D6.94的内在清除率值显著增加，并且八个变体（CYP2D6.88、CYP2D6.89、CYP2D6.91、CYP2D6.97、V342M、R344Q、F219S和F164L）无显著差异。此外，23种CYP2D6等位基因亚型对吉非替尼表现出底物抑制趋势。
作为对上述所有等位基因进行吉非替尼代谢的首次研究，这些全面的数据可能有助于吉非替尼代谢的临床评估，也可为临床环境中吉非替尼的个体化治疗提供参考。
