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. 2019 Jul;43(3):460-474.
doi: 10.1016/j.jgr.2018.04.003. Epub 2018 Apr 28.

Impact of NR1I2, adenosine triphosphate-binding cassette transporters genetic polymorphisms on the pharmacokinetics of ginsenoside compound K in healthy Chinese volunteers

Luping Zhou  1   2 , Lulu Chen  1   2 , Yaqin Wang  1   2 , Jie Huang  3 , Guoping Yang  3 , Zhirong Tan  1   2 , Yicheng Wang  1   2 , Jianwei Liao  1   2 , Gan Zhou  1   2 , Kai Hu  4 , Zhenyu Li  5 , Dongsheng Ouyang  1   2   6
Affiliations

Impact of NR1I2, adenosine triphosphate-binding cassette transporters genetic polymorphisms on the pharmacokinetics of ginsenoside compound K in healthy Chinese volunteers

Luping Zhou et al. J Ginseng Res. 2019 Jul.

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 (Cmax) of CK. The area under the curve from zero to the time of the last quantifiable concentration (AUClast) of CK was decreased in NR1I2 rs1464602 and rs2472682 homozygous carriers, while Cmax 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: Genetic polymorphisms; Ginsenoside compound K; Pharmacokinetics; Transporters.

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Figures

Fig. 1
Fig. 1
Distribution of the CK pharmacokinetic parameters of the ABCC4 (rs1751034 and rs1189437), and NR1I2 (rs1464602 and rs2472682) gene variants. (A) CK Cmax/Dose. (B) CK AUClast/Dose. The mean is represented by a horizontal line through the given point. AUClast, area under the plasma concentration–time curve from zero to the time of the last quantifiable concentration; CK, ginsenoside compound K; Cmax, maximum concentrations.
Fig. 2
Fig. 2
Distribution of the 20(S)-PPD pharmacokinetic parameters of the ABCC4 (rs1151471, rs1751034, and rs1189437) and CFTR (rs2283054) gene variants. (A) 20(S)-PPD Cmax/Dose. (B) 20(S)-PPD AUClast/Dose. The mean is represented by a horizontal line through the given point. AUClast, area under the plasma concentration-time curve from zero to the time of the last quantifiable concentration; Cmax, maximum concentrations; PPD, protopanaxadiol.
Fig. 3
Fig. 3
Distribution of the pharmacokinetic parameters ratio of 20(S)-PPD to CK of the ABCC3 (rs12051822), ABCC4 (rs4148546, rs1151471, rs1751034, and rs1189437), and CFTR (rs2283054) gene variants. (A) Cmax/Dose ratio. (B) AUClast/Dose ratio. The mean is represented by a horizontal line through the given point. AUClast, area under the plasma concentration-time curve from zero to the time of the last quantifiable concentration; CK, ginsenoside compound K; Cmax, maximum concentrations; PPD, protopanaxadiol.
Fig. 4
Fig. 4
Pharmacokinetic profiles of CK after a single oral dose of CK in 54 healthy Chinese volunteers with different ABCC4, CFTR, or NR1I2 genotypes (mean ± SD). CK, ginsenoside compound K; SD, standard deviation. All below error bars have been omitted for clarity.
Fig. 5
Fig. 5
Pharmacokinetic profiles of 20(S)-PPD after a single oral dose of CK in 54 healthy Chinese volunteers with different ABCC4 or CFTR genotypes (mean ± SD). CK, ginsenoside compound K; PPD, protopanaxadiol; SD, standard deviation. All below error bars have been omitted for clarity.
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