Effects of CYP2C9*1/*3 and *1/*13 on the pharmacokinetics of losartan and its active metabolite E-3174

Objective: The effects of CYP2C9*1/*3 and *1/*13 genotypes were evaluated on the pharmacokinetics of losartan and its active metabolite, E-3174, in Korean subjects. Methods: Losartan (50 mg) was administered in 43 Korean volunteers with different CYP2C9 genotypes (CYP2C9*1/*1, *1/*3 and *1/*13). Losartan and E-3174 levels in the plasma and urine were analyzed by HPLC using fluorescence. Results: The CYP2C9*1/*13 subjects showed lower oral clearance (p < 0.001) and greater AUC _0-∞ (p < 0.01) of losartan and higher C _max (p < 0.01) and longer half-life (p < 0.001) of E-3174 than the CYP2C9*1/*1 subjects, but AUC _0-∞ of E-3174 was not different. The CYP2C9*1/*3 subjects showed lower oral clearance (p < 0.001) of losartan and higher C _max (p < 0.01) and longer half-life (p < 0.01) of E-3174 than the CYP2C9*1/*1 subjects. However, AUC _0-∞ of losartan was greater in CYP2C9*1/*3 subjects than in CYP2C9*1/*1, but these results were not significant (p < 0.05, but statistical power < 0.8). In addition, AUC _0-∞ of E-3174 was not different. There were no significant differences in pharmacokinetic parameters between the CYP2C9*1/*13 and CYP2C9*1/*3 subjects. Conclusion: These results suggest that CYP2C9*1/*3 and CYP2C9*1/*13 are similarly associated with decreased formation of E-3174 from losartan, but the clinical effects of losartan may not be reduced by CYP2C9*1/*3 and CYP2C9*1/*13.