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


CONCLUSIONS
Silymarin inhibits the metabolism of losartan to E-3174, with the magnitude of the interaction differing in individuals with different CYP2C9 genotypes.
Han
Yang
Y
Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, P.R. China.
Guo
Dong
D
Chen
Yao
Y
Chen
Yu
Y
Tan
Zhi-Rong
ZR
Zhou
Hong-Hao
HH
D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002681:China; D065729:Cytochrome P-450 CYP2C9; D005838:Genotype; D006801:Humans; D019808:Losartan / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D012016:Reference Values; D012838:Silymarin / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D012838:Silymarin; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D019808:Losartan