Effect of CYP2C9 genetic polymorphism and breviscapine on losartan pharmacokinetics in healthy subjects

Abstract

1. Breviscapine was an active ingredient of flavonoid glycosides. Our present study was conducted to evaluate the impact of breviscapine on the pharmacokinetics of losartan and its active metabolite E-3174, and that relationship with the gene polymorphism of CYP2C9 in healthy Chinese volunteers, to provide a basis for clinical rational drug use.

2. The genotypes of 217 healthy Chinese subjects were determined using PCR-RFLP. Twelve healthy subjects were selected and were known CYP2C9 genotypes (six CYP2C9*1/*3 and six CYP2C9*1/*1) in a two-phase randomised crossover design study. These subjects were given daily doses of 120 mg (40 mg, three times a day) of breviscapine or a placebo for 14 days, followed by 50 mg losartan on day 15.

3. Compared with individuals carrying the CYP2C9*1/*1 genotype, the CYP2C9*1/*3 genotype showed an increase in the AUC_(0–36) (833.6 ± 379.8 ng h ml⁻¹ vs. 526.1 ± 140.1 ng h ml⁻¹, p < 0.05) and a decrease in the MR (the metabolic ratio of losartan, AUC_E-3174/AUC_losartan) (2.67 ± 1.40 vs. 4.56 ± 0.83, p < 0.05) of losartan during the placebo treatment phase. Individuals with genotype CYP2C9*1/*3 showed a significant increase in AUC_(0–36) (2335 ± 851.8 ng h ml⁻¹ vs. 1927 ± 949.5 ng h ml⁻¹, p < 0.05) and AUC_(0–∞) (2363 ± 875.6 ng h ml⁻¹ vs. 1966 ± 966.1 ng h ml⁻¹, p < 0.05) of E-3174 after breviscapine treatment compared to the placebo group.

4. In healthy subjects, breviscapine had no significant effect on the pharmacokinetics of losartan. The activity of CYP2C9 enzyme to losartan metabolism was more significant in subjects with CYP2C9*1/*3 than those with CYP2C9*1/*1 genotype.

Keywords:

• Breviscapine
• losartan
• E-3174
• CYP2C9
• polymorphism
• pharmacokinetics

Acknowledgements

We appreciate all subjects for participating in our clinical trial and staff at the Affiliated Hospital of Dali University for their assistance.

Ethical approval

This study was approved by the Medical Ethics Committee of Dali University (Grant Number: 2016047) and was conducted by the Declaration of Helsinki for biomedical research involving human subjects.

Author contributions

YL, HXH, YD are the designers of this study. HXH, TZ, AXE and HW performed all the matters of this study. Among them, HXH, AXE, HW and TZ perform data collection and analysis, AXE, HW is responsible for purchasing reagents and materials related to the experiment. YL, YD, and YZ provide us with experimental technical support and guidance. YD, HXH, TZ, HW is responsible for patient recruitment, drug administration, and blood collection. YL supervises and manages the entire trial process. HXH, YL drafted the initial manuscript and all authors commented on previous versions of the manuscript. HXH, HW, YYZ, YL played an important role in the revision of this manuscript. All authors read and approved the final manuscript.

Disclosure statement

The authors have no conflicts of interest to declare that are relevant to the content of this article.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Moral declaration

The paper was not considered by another journal, and the results here have not been published before. All authors met the criteria for authorship and agreed to publish.

Data availability statement

The datasets used and/or analysed during the current study are available from the corresponding author on a reasonable request.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [grant number 81360511].