Pharmacokinetics of losartan and its metabolite E‐3174 in relation to the CYP2C9 genotype

Background And Aim Losartan is metabolized by polymorphic CYP2C9 to E‐3174. Our aim was to evaluate the pharmacokinetics of losartan and E‐3174 in relation to the CYP2C9 genotype. Methods A 50‐mg oral dose of losartan was given to 22 Swedish volunteers with different CYP2C9 genotypes. Losartan and E‐3174 were analyzed by HPLC in plasma and urine samples collected up to 24 hours after drug intake. Furthermore, losartan and E‐3174 were analyzed in 8‐hour urine samples collected from 17 Spanish subjects after a single oral dose of 25 mg losartan. Results The maximum plasma concentration of E‐3174 was significantly ( P < .05) lower in the CYP2C9*1/*3 (n = 5) and CYP2C9*2/*3 (n = 4) groups compared with the CYP2C9*1/*1 (n = 6) and CYP2C9*1/*2 (n = 3) groups and extremely low in 1 subject with the CYP2C9*3/*3 genotype. The ratio of the total losartan area under the plasma concentration–time curve (AUC) to the total E‐3174 AUC (AUC losartan /AUC E‐3174 ) was higher in the subject with the CYP2C9*3/*3 genotype (30‐fold) and also in the CYP2C9*1/*3 and *2/*3 groups (approximately 2‐ and 3‐fold, respectively) compared with the CYP2C9*1/*1 group. The plasma ratios correlated significantly with the 0‐ to 8‐hour urinary losartan/E‐3174 ratios. Among the total of 39 subjects, the urinary ratio was significantly higher in subjects with the CYP2C9*1/*3 (n = 10) and *2/*3 (n = 4) genotypes than in those with the CYP2C9*1/*1 genotype (n = 11; P < .01) and approximately 40‐fold higher in subjects with the CYP2C9*3/*3 genotype (n = 3). Conclusion The CYP2C9*3 allele was shown to be associated with decreased formation of E‐3174 from losartan. The significant differences between genotypes in plasma and urine losartan/E‐3174 ratios and the good correlation between the plasma and urine ratios suggest that the losartan/E‐3174 ratio in 0‐ to 8‐hour urine specimens may serve as a phenotyping assay for CYP2C9 activity. Further studies in larger populations will be required to establish this. Clinical Pharmacology & Therapeutics (2002) 71 , 89–98; doi: 10.1067/mcp.2002.121216