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 eval- uate 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 geno- types. 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. (Clin Pharmacol Ther 2002;71:89-98.) Ümit Yasar, MD, Cecilia Forslund-Bergengren, MD, Gunnel Tybring, PhD, Pedro Dorado, Adrián LLerena, MD, PhD, Folke Sjöqvist, MD, PhD, Erik Eliasson, MD, PhD, and Marja-Liisa Dahl, MD, PhD Stockholm, Sweden, and Badajoz, Spain From the Department of Medical Laboratory Sciences and Technol- ogy, Division of Clinical Pharmacology, Karolinska Institutet at Huddinge University Hospital, Stockholm; and the Department of Pharmacology and Psychiatry, Medical School, University of Extremadura, Badajoz. Supported by grants from the Swedish Medical Research Council (3902), the Swedish Society of Medicine, and the Karolinska Institutet. Dr Yasar is the recipient of a Turkish Higher Educa- tion Council PhD scholarship, and Dr Eliasson is the recipient of a Merck Sharp & Dohme fellowship in clinical pharmacol- ogy. The Spanish study and fellowship of Mr Dorado were sup- ported by the Ministry of Health, Spain (Instituto Carlos III, Fis01/0699). Presented in part at the Seventh World Conference on Clinical Phar- 89 macology and Therapeutics and the Fourth Congress of the Euro- pean Association for Clinical Pharmacology and Therapeutics, Florence, Italy, July 15-20, 2000, and at the Twelfth International Symposium on Microsomes and Drug Oxidations, Stresa, Italy, July 10-14, 2000. Received for publication March 21, 2001; accepted Oct 17, 2001. Reprint requests: Marja-Liisa Dahl, MD, PhD, Department of Med- ical Sciences, Clinical Pharmacology, University Hospital, SE- 75185, Uppsala, Sweden. E-mail: Marja-Liisa.Dahl@medsci.uu.se Copyright © 2002 by the American Society for Clinical Pharmacol- ogy and Therapeutics. 0009-9236/2002/$35.00 + 0 13/1/121216 doi:10.1067/mcp.2002.121216