Effect of silymarin on the pharmacokinetics of losartan and its active metabolite E-3174 in healthy Chinese volunteers.

PURPOSE: To investigate the effects of silymarin on the pharmacokinetics of losartan and its active metabolite E-3174 and its relationship with CYP2C9 genotypes. METHODS: Twelve healthy adult men of known CYP2C9 genotype (six CYP2C9*1/*1 and six CYP2C9*1/*3) were recruited in a two-phase randomized crossover design study. The pharmacokinetics of losartan and E-3174 were measured before and after a 14-day treatment with 140 mg of silymarin three times daily. RESULTS: The area under the plasma concentration-time curve (AUC) of losartan increased significantly following a 14-day silymarin treatment in subjects with the CYP2C9*1/*1 genotype, but not in those with the CYP2C9*1/*3 genotype. The AUC of E-3174 decreased significantly with a silymarin pretreatment in both CYP2C9*1/*1 and the CYP2C9*1/*3 subjects. The metabolic ratio of losartan (ratio of AUC(0-infinity) of E-3174 to AUC(0-infinity) of losartan) decreased significantly after a 14-day treatment with silymarin in individuals with the CYP2C9*1/*1 genotype (p < 0.05), but not in those with the CYP2C9*1/*3 genotype (p = 0.065). CONCLUSION: Silymarin inhibits the metabolism of losartan to E-3174, with the magnitude of the interaction differing in individuals with different CYP2C9 genotypes.