Effect of the single CYP2C9*3 allele on pharmacokinetics and pharmacodynamics of losartan in healthy Japanese subjects |
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Authors: | Kazuishi Sekino Takahiro Kubota Yuko Okada Yasuhiko Yamada Koujirou Yamamoto Ryuya Horiuchi Kenjirou Kimura Tatsuji Iga |
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Affiliation: | (1) Department of Pharmacy, Faculty of Medicine, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;(2) Division of Nephrology and Hypertension, Department of Clinical Pharmacology, Gunma University School of Medicine, Gunma, Japan;(3) Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan |
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Abstract: | Objective Losartan is metabolized to the active carboxylic acid metabolite EXP3174 by CYP2C9. In this study, we determined the effects of the single CYP2C9*3 variant on the pharmacokinetics and pharmacodynamics of losartan.Methods Seven healthy Japanese subjects (CYP2C9*1/*1, n=4 and CYP2C9*1/*3, n=3) were phenotyped with a single dose of losartan (25 mg). Blood and urine samples were collected and assayed for losartan and EXP3174. Blood pressure and pulse rate were also measured using a sphygmomanometer.Results The maximum plasma concentration of EXP3174 was significantly (P<0.05) lower in the CYP2C9*1/*3 (n=3) group than in the CYP2C9*1/*1 (n=4) group. Diastolic blood pressure in the CYP2C9*1/*1 group, but not that in the CYP2C9*1/*3 group except for at 6 h and 8 h, was reduced from 1.5 h to 12 h compared with the baseline level. Systolic blood pressure in the CYP2C9*1/*1 group, but not that in the CYP2C9*1/*3 group, was reduced from 1 h to 12 h compared with the baseline level. The metabolic ratio (MR) of EXP3174 concentration to the losartan concentration in plasma at 6 h post-dosing and the 4-h to 8-h urinary EXP3174/losartan MR were significantly lower in the CYP2C9*1/*3 group than in the CYP2C9*1/*1 group. The plasma 6-h MR and the 4-h to 8-h urinary MR were significantly (P<0.05) correlated with the plasma AUC ratio (AUCEXP3174/AUClosartan), with Spearman rank correlation coefficients of 0.75 and 0.89, respectively.Conclusion The single CYP2C9*3 variant reduces the metabolism of losartan and its hypotensive effect. Plasma MR, as well as urine MR, may be useful for phenotyping assays of CYP2C9 activity. |
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Keywords: | CYP2C9 phenotyping Losartan Pharmacodynamics |
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