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

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, AUCE-3174/AUClosartan) (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.