Dual kinetics of OATP2B1: Inhibitory potency and pH-dependence of OATP2B1 inhibitors |
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| Affiliation: | 1. Graduate School of Pharmaceutical Sciences, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo, 105–8512, Japan;2. School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba, 274–8555, Japan;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, Kanagawa, 210-9501, Japan;3. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan;4. Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan;1. Department of Pharmacy, Fukuoka City Hospital, Fukuoka City Hospital Organization, Local Incorporated Administrative Agency, Fukuoka, Japan;2. Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan;3. Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan;1. Research and Development, Janssen Pharmaceutical K.K., Tokyo, Japan;2. Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, Japan;3. Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium;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 |
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| Abstract: | Organic anion transporting polypeptide (OATP) 2B1 is expressed in the intestine and liver, and OATP2B1-mediated transport of estrone 3-sulfate is pH-dependent and consists of: the high-affinity component (Hc) and low-affinity component (Lc). This study aimed to evaluate the influence of pH on the transport kinetics of each component, along with the inhibitory nature of ten OATP2B1 inhibitors. The Michaelis constants (Km) were 4-fold and 1.5-fold lower at pH 6.3 than at pH 7.4, for Hc and Lc respectively. The inhibitory potencies of diclofenac, indomethacin, and ibuprofen towards Hc were 1.5–4.3 fold lower at pH 6.3 than at pH 7.4. Contrastingly, inhibitory potencies towards Lc were 9.0–52 fold lower at pH 7.4. Similarly, the inhibitory effect of naproxen was stronger towards Hc at pH 6.3 and towards Lc at pH 7.4. On the other hand, celecoxib selectively inhibited Lc transport at pH 7.4. Rifampicin inhibited both components at pH 6.3 and 7.4 to a similar extent, while bromosulphophthalein, naringin, and gefitinib selectively inhibited Hc irrespective of pH. Fexofenadine inhibited neither component. In conclusion, the transport affinities of both Hc and Lc were enhanced under acidic conditions. The influence of pH on the inhibitory potency towards each component varied among the inhibitors. |
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| Keywords: | OATP2B1 pH-dependent High- and low-affinity components Bimodal kinetics Drug-drug interaction NSAIDs |
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