Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Impact of NR1I2, adenosine triphosphate-binding cassette transporters genetic polymorphisms on the pharmacokinetics of ginsenoside compound K in healthy Chinese volunteers

  • Zhou, Luping (Department of Clinical Pharmacology, Xiangya Hospital, Central South University) ;
  • Chen, Lulu (Department of Clinical Pharmacology, Xiangya Hospital, Central South University) ;
  • Wang, Yaqin (Department of Clinical Pharmacology, Xiangya Hospital, Central South University) ;
  • Huang, Jie (Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University) ;
  • Yang, Guoping (Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University) ;
  • Tan, Zhirong (Department of Clinical Pharmacology, Xiangya Hospital, Central South University) ;
  • Wang, Yicheng (Department of Clinical Pharmacology, Xiangya Hospital, Central South University) ;
  • Liao, Jianwei (Department of Clinical Pharmacology, Xiangya Hospital, Central South University) ;
  • Zhou, Gan (Department of Clinical Pharmacology, Xiangya Hospital, Central South University) ;
  • Hu, Kai (Department of Neurology, Xiangya Hospital, Central South University) ;
  • Li, Zhenyu (Department of Cardiology, Xiangya Hospital, Central South University) ;
  • Ouyang, Dongsheng (Department of Clinical Pharmacology, Xiangya Hospital, Central South University)
  • Received : 2018.02.07
  • Accepted : 2018.04.17
  • Published : 2019.07.15
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Abstract

Background: Ginsenoside compound K (CK) is a promising drug candidate for rheumatoid arthritis. This study examined the impact of polymorphisms in NR1I2, adenosine triphosphate-binding cassette (ABC) transporter genes on the pharmacokinetics of CK in healthy Chinese individuals. Methods: 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. Results: ABCC4 rs1751034 TT and rs1189437 TT were associated with increased exposure of CK and decreased exposure of 20(S)-PPD, whereas CFTR rs4148688 heterozygous carriers had the lowest maximum concentration ($C_{max}$) of CK. The area under the curve from zero to the time of the last quantifiable concentration ($AUC_{last}$) of CK was decreased in NR1I2 rs1464602 and rs2472682 homozygous carriers, while $C_{max}$ was significantly reduced only in rs2472682. ABCC4 rs1151471 and CFTR rs2283054 influenced the pharmacokinetics of 20(S)-PPD. In addition, several variations in ABCC2, ABCC4, CFTR, and NR1I2 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. Conlusion: ABCC4 rs1751034 and rs1189437 affected the pharmacokinetics of both CK and 20(S)-PPD. NR1I2 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.

Keywords

References

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