Keita Hirai1, Yuto Yamada1, Hideki Hayashi2, Masaki Tanaka1, Kohei Izumiya1, Masayuki Suzuki1, Misa Yoshizawa1, Hideaki Moriwaki3, Takehide Akimoto4, Daiki Tsuji1, Kazuyuki Inoue1, Kunihiko Itoh5. 1. Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan. 2. Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan; Laboratory of Pharmacy Practice and Social Science, Gifu Pharmaceutical University, 1-25-4 Daigakunishi, Gifu 501-1196, Japan. 3. Department of Cardiology, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka 420-8527, Japan. 4. Department of Cardiovascular Surgery, Shizuoka General Hospital, 4-27-1, Kita-ando, Aoi-ku, Shizuoka 420-8527, Japan. 5. Department of Clinical Pharmacology & Genetics, School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka 422-8526, Japan. Electronic address: itohk@u-shizuoka-ken.ac.jp.
Abstract
INTRODUCTION: Warfarin is characterized by a large inter-individual variability in dosage requirement. This study aimed to analyze the contribution of the CYP4F2 genetic polymorphism and plasma vitamin K concentration on the warfarin pharmacodynamics in patients and to clarify the plasma vitamin K concentration affecting warfarin sensitivity index in rats. MATERIALS AND METHODS: Genetic analyses of selected genes were performed and plasma concentrations of warfarin, vitamin K1 (VK1) and menaquinone-4 (MK-4) were measured in 217 Japanese patients. We also assessed the association of plasma VK1 and MK-4 concentrations with the warfarin sensitivity index (INR/Cp) in rats. RESULTS: Patients with the CYP4F2 (rs2108622) TT genotype had significantly higher plasma VK1 and MK-4 concentrations than those with CC and CT genotypes. The multiple linear regression model including VKORC1, CYP4F2, and CYP2C9 genetic variants, age, and weight could explain 42% of the variability in warfarin dosage. The contribution of CYP4F2 polymorphism was estimated to be 2.2%. In contrast, plasma VK1 and MK-4 concentrations were not significantly associated with warfarin dosage in patients. Nevertheless, we were able to demonstrate that the warfarin sensitivity index was attenuated and negatively correlated with plasma VK1 concentration by the oral administration of VK1 in rats, as it resulted in a higher VK1 concentration than that in patients. CONCLUSIONS: The plasma VK1 and MK-4 concentrations are significantly influenced by CYP4F2 genetic polymorphism but not associated with warfarin therapy at the observed concentration in Japanese patients. The CYP4F2 polymorphism is poorly associated with inter-individual variability of warfarin dosage requirement.
INTRODUCTION:Warfarin is characterized by a large inter-individual variability in dosage requirement. This study aimed to analyze the contribution of the CYP4F2 genetic polymorphism and plasma vitamin K concentration on the warfarin pharmacodynamics in patients and to clarify the plasma vitamin K concentration affecting warfarin sensitivity index in rats. MATERIALS AND METHODS: Genetic analyses of selected genes were performed and plasma concentrations of warfarin, vitamin K1 (VK1) and menaquinone-4 (MK-4) were measured in 217 Japanese patients. We also assessed the association of plasma VK1 and MK-4 concentrations with the warfarin sensitivity index (INR/Cp) in rats. RESULTS:Patients with the CYP4F2 (rs2108622) TT genotype had significantly higher plasma VK1 and MK-4 concentrations than those with CC and CT genotypes. The multiple linear regression model including VKORC1, CYP4F2, and CYP2C9 genetic variants, age, and weight could explain 42% of the variability in warfarin dosage. The contribution of CYP4F2 polymorphism was estimated to be 2.2%. In contrast, plasma VK1 and MK-4 concentrations were not significantly associated with warfarin dosage in patients. Nevertheless, we were able to demonstrate that the warfarin sensitivity index was attenuated and negatively correlated with plasma VK1 concentration by the oral administration of VK1 in rats, as it resulted in a higher VK1 concentration than that in patients. CONCLUSIONS: The plasma VK1 and MK-4 concentrations are significantly influenced by CYP4F2 genetic polymorphism but not associated with warfarin therapy at the observed concentration in Japanese patients. The CYP4F2 polymorphism is poorly associated with inter-individual variability of warfarin dosage requirement.
Authors: Elisa Danese; Sara Raimondi; Martina Montagnana; Angela Tagetti; Taimour Langaee; Paola Borgiani; Cinzia Ciccacci; Antonio J Carcas; Alberto M Borobia; Hoi Y Tong; Cristina Dávila-Fajardo; Mariana Rodrigues Botton; Stephane Bourgeois; Panos Deloukas; Michael D Caldwell; Jim K Burmester; Richard L Berg; Larisa H Cavallari; Katarzyna Drozda; Min Huang; Li-Zi Zhao; Han-Jing Cen; Rocio Gonzalez-Conejero; Vanessa Roldan; Yusuke Nakamura; Taisei Mushiroda; Inna Y Gong; Richard B Kim; Keita Hirai; Kunihiko Itoh; Carlos Isaza; Leonardo Beltrán; Enrique Jiménez-Varo; Marisa Cañadas-Garre; Alice Giontella; Marianne K Kringen; Kari Bente Foss Haug; Hye Sun Gwak; Kyung Eun Lee; Pietro Minuz; Ming Ta Michael Lee; Steven A Lubitz; Stuart Scott; Cristina Mazzaccara; Lucia Sacchetti; Ece Genç; Mahmut Özer; Anil Pathare; Rajagopal Krishnamoorthy; Andras Paldi; Virginie Siguret; Marie-Anne Loriot; Vijay Kumar Kutala; Guilherme Suarez-Kurtz; Jamila Perini; Josh C Denny; Andrea H Ramirez; Balraj Mittal; Saurabh Singh Rathore; Hersh Sagreiya; Russ Altman; Mohamed Hossam A Shahin; Sherief I Khalifa; Nita A Limdi; Charles Rivers; Aditi Shendre; Chrisly Dillon; Ivet M Suriapranata; Hong-Hao Zhou; Sheng-Lan Tan; Vacis Tatarunas; Vaiva Lesauskaite; Yumao Zhang; Anke H Maitland-van der Zee; Talitha I Verhoef; Anthonius de Boer; Monica Taljaard; Carlo Federico Zambon; Vittorio Pengo; Jieying Eunice Zhang; Munir Pirmohamed; Julie A Johnson; Cristiano Fava Journal: Clin Pharmacol Ther Date: 2019-02-17 Impact factor: 6.875
Authors: Nicholas T Au; Tove Ryman; Allan E Rettie; Scarlett E Hopkins; Bert B Boyer; Jynene Black; Jacques Philip; Joseph Yracheta; Alison E Fohner; Morayma Reyes; Timothy A Thornton; Melissa A Austin; Kenneth E Thummel Journal: Mol Nutr Food Res Date: 2017-12-29 Impact factor: 5.914
Authors: Nicholas T Au; Morayma Reyes; Bert B Boyer; Scarlett E Hopkins; Jynene Black; Diane O'Brien; Alison E Fohner; Joe Yracheta; Timothy Thornton; Melissa A Austin; Wylie Burke; Kenneth E Thummel; Allan E Rettie Journal: PLoS One Date: 2017-04-04 Impact factor: 3.240