Comparison of the inhibitory properties of the fruit component naringenin and its glycosides against OATP1A2 genetic variants |
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| Affiliation: | 1. Division of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan;2. Department of Clinical Pharmacy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan;3. Division of Molecular Targeting Therapeutics, School of Pharmacy, Nihon University, 7-7-1, Narashinodai, Funabashi-shi, Chiba, 274-8555, Japan;4. Department of Pharmacy, Keio University Hospital, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan;1. Preclinical Research Unit, Drug Research Division, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka, 554-0022, Japan;2. Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan;1. Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Doshisha Women''s College of Liberal Arts, Kyotanabe, 610-0395, Japan;2. Division of Medical Safety Science, National Institute of Health Sciences, Kawasaki, 210-9501, Japan;3. Department of Clinical Oncology, Kawasaki Medical School, Kurashiki, 701-0192, Japan;4. Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan;5. Department of Gastrointestinal Surgery, Niigata Cancer Center Hospital, Niigata, 951-8566, Japan;6. Mitsugi General Hospital, Onomichi, 722-0393, Japan;7. Department of Surgery, Sanjo General Hospital, Sanjo, 955-0055, Japan;1. Central Institute for Experimental Animals, Kawasaki, 210-0821, Japan;2. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan;3. Institut de Chimie Organique et Analytique, University of Orléans, 45067, Orléans Cedex 2, France;1. Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, 980-8578, Japan;2. Division of Risk Assessment, National Institute of Health Sciences, Tonomachi 3-25-26, Kawasaki-ku, Kawasaki, 210-9501, Japan;3. Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526 Japan;4. Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co, Ltd, 463-10 Kagasuno, Kawauchi-cho, Tokushima, 771-0192, Japan;1. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Japan;2. Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima-city, Japan |
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| Abstract: | Non-synonymous genetic variants of organic anion-transporting polypeptide (OATP) 1A2 with altered transport activity have been identified. Naringin and narirutin, which are found in grapefruit, and their aglycon naringenin inhibit OATP1A2. However, their inhibitory effects on OATP1A2 variants have not been investigated, nor has the influence of their molecular structure, such as the number of sugar moieties, on their inhibitory potency. This study aimed to investigate the inhibitory effects of naringenin, its monosaccharide glycoside prunin, and its disaccharide glycosides naringin and narirutin on fexofenadine (FEX) uptake by OATP1A2 variants (Ile13Thr, Asn128Tyr, Ala187Thr, and Thr668Ser).Naringin, narirutin, and prunin inhibited FEX (0.3 μM) uptake by all of the examined OATP1A2 variants in a concentration-dependent manner. Compared with those for the wild type, the inhibition constants (Ki) of naringin, narirutin, and prunin for the Ala187Thr variant were significantly increased by 3.36-fold, 7.55-fold, and 10.6-fold, respectively. Naringenin inhibited all of the OATP1A2 variants, except Ala187Thr, concentration-dependently. The order of inhibitory potency was as follows for all variants: aglycone > monosaccharide glycoside > disaccharide glycosides.These results suggest that the Ala187Thr variant is less vulnerable to inhibition by naringenin and its glycosides. Moreover, greater glycosylation of naringenin reduces its inhibitory potency against OATP1A2. |
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| Keywords: | OATP1A2 Genetic variants Naringin Narirutin Prunin Naringenin Citrus fruits Food-drug interaction |
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