Kim Serim, Seo Jong Do, Yun Yeo-Min, Kim Hanah, Kim Tae-Eun, Lee Taeheon, Lee Tae-Rim, Lee Jun Hyung, Cho Eun-Hae, Ki Chang-Seok
Department of Laboratory Medicine, Shinwon Medical Foundation, Gwangmyeong-si, South Korea.
Department of Laboratory Medicine, Konkuk University Medical Center, Seoul, South Korea.
Front Genet. 2022 May 19;13:836970. doi: 10.3389/fgene.2022.836970. eCollection 2022.
Statins are the most popular agents for the primary and secondary prevention of cardiovascular disease; however, the pharmacokinetic parameters and associated genetic factors in the Korean population have not been fully elucidated. This study explored the pharmacokinetic properties of atorvastatin and the association between genetic variations and atorvastatin pharmacokinetics in healthy Korean subjects. Atorvastatin (80 mg) was administered to 35 healthy Korean volunteers. Plasma levels of atorvastatin and its metabolites were measured sequentially using liquid chromatography-tandem mass spectrometry from 0 to 24 h after atorvastatin administration. Customized next-generation sequencing analysis was performed covering all coding exons of 15 genes, as well as 46 single-nucleotide variants in 29 genes related to statin pharmacokinetics. The mean area under the concentration-time (AUC) and C (maximum peak concentration) were 269.0 ng/ml∙h and 84.3 ng/ml, respectively, which were approximately two times higher than those reported in Caucasians. Genetic analysis revealed that eight genetic variants in , and contributed to the AUC of atorvastatin. The atorvastatin AUC prediction model was developed based on age and eight genetic variants using multivariate linear regression (adjusted = 0.878, < 0.0001). This study shows that the pharmacokinetic properties of atorvastatin in Koreans are different from those in Caucasians and that atorvastatin AUC could be predicted based on age and eight genetic variants of and .
他汀类药物是用于心血管疾病一级和二级预防的最常用药物；然而，韩国人群中的药代动力学参数及相关遗传因素尚未完全阐明。本研究探讨了阿托伐他汀在健康韩国受试者中的药代动力学特性以及基因变异与阿托伐他汀药代动力学之间的关联。给35名健康韩国志愿者服用阿托伐他汀（80毫克）。在服用阿托伐他汀后0至24小时，使用液相色谱 - 串联质谱法依次测量阿托伐他汀及其代谢物的血浆水平。进行了定制的下一代测序分析，涵盖15个基因的所有编码外显子，以及与他汀类药物药代动力学相关的29个基因中的46个单核苷酸变异。浓度 - 时间曲线下平均面积（AUC）和C（最大峰值浓度）分别为269.0纳克/毫升∙小时和84.3纳克/毫升，约为高加索人报道值的两倍。基因分析显示， 、 和 中的八个基因变异对阿托伐他汀的AUC有影响。使用多元线性回归基于年龄和八个基因变异建立了阿托伐他汀AUC预测模型（调整后 = 0.878， < 0.0001）。本研究表明，阿托伐他汀在韩国人中的药代动力学特性与高加索人不同，并且可以基于年龄以及 和 的八个基因变异来预测阿托伐他汀的AUC。
