Zhou Luping, Chen Lulu, Wang Yaqin, Huang Jie, Yang Guoping, Tan Zhirong, Wang Yicheng, Liao Jianwei, Zhou Gan, Hu Kai, Li Zhenyu, Ouyang Dongsheng
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
Institute of Clinical Pharmacology, Central South University, Changsha, China.
J Ginseng Res. 2019 Jul;43(3):460-474. doi: 10.1016/j.jgr.2018.04.003. Epub 2018 Apr 28.
Ginsenoside compound K (CK) is a promising drug candidate for rheumatoid arthritis. This study examined the impact of polymorphisms in , adenosine triphosphate-binding cassette (ABC) transporter genes on the pharmacokinetics of CK in healthy Chinese individuals.
Forty-two targeted variants in seven genes were genotyped in 54 participants using Sequenom MassARRAY system to investigate their association with major pharmacokinetic parameters of CK and its metabolite 20(S)-protopanaxadiol (PPD). Subsequently, molecular docking was simulated using the AutoDock Vina program.
rs1751034 TT and rs1189437 TT were associated with increased exposure of CK and decreased exposure of 20(S)-PPD, whereas rs4148688 heterozygous carriers had the lowest maximum concentration (C) of CK. The area under the curve from zero to the time of the last quantifiable concentration (AUC) of CK was decreased in rs1464602 and rs2472682 homozygous carriers, while C was significantly reduced only in rs2472682. rs1151471 and rs2283054 influenced the pharmacokinetics of 20(S)-PPD. In addition, several variations in , , , and had minor effects on the pharmacokinetics of CK. Quality of the best homology model of multidrug resistance protein 4 (MRP4) was assessed, and the ligand interaction plot showed the mode of interaction of CK with different MRP4 residues.
rs1751034 and rs1189437 affected the pharmacokinetics of both CK and 20(S)-PPD. rs1464602 and rs2472682 were only associated with the pharmacokinetics of CK. Thus, these hereditary variances could partly explain the interindividual differences in the pharmacokinetics of CK.
人参皂苷Compound K（CK）是一种有前景的类风湿性关节炎候选药物。本研究考察了三磷酸腺苷结合盒（ABC）转运蛋白基因多态性对健康中国个体中CK药代动力学的影响。
使用Sequenom MassARRAY系统对54名参与者的7个基因中的42个靶向变异进行基因分型，以研究它们与CK及其代谢物20（S）-原人参二醇（PPD）的主要药代动力学参数的关联。随后，使用AutoDock Vina程序模拟分子对接。
rs1751034 TT和rs1189437 TT与CK暴露增加及20（S）-PPD暴露减少相关，而rs4148688杂合携带者的CK最高浓度（Cmax）最低。rs1464602和rs2472682纯合携带者中，CK从零至最后可定量浓度时间的曲线下面积（AUC）降低，而仅rs2472682中的Cmax显著降低。rs1151471和rs2283054影响20（S）-PPD的药代动力学。此外，ABCB1、ABCC2、ABCC3和ABCG2中的若干变异对CK的药代动力学有轻微影响。评估了多药耐药蛋白4（MRP4）最佳同源模型的质量，配体相互作用图显示了CK与不同MRP4残基的相互作用模式。
rs1751034和rs1189437影响CK和20（S）-PPD的药代动力学。rs1464602和rs2472682仅与CK的药代动力学相关。因此，这些遗传变异可部分解释CK药代动力学的个体间差异。
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