Phenolsulfonphthalein as a surrogate substrate to assess altered function of the prostaglandin transporter SLCO2A1 |
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| Institution: | 1. Laboratory of Membrane Transport for Biopharmaceutics, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Japan;2. Laboratory of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Japan;1. Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan;2. Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan;3. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Japan;1. Central Institute for Experimental Animals, Kawasaki, Japan;2. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, 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 Pharmacy, Kyushu University Hospital, Fukuoka, Japan;2. Laboratory of Pharmaceutics, Department of Biomedical Pharmaceutics, Gifu Pharmaceutical University, Gifu, Japan;3. Center for the Study of Global Infection, Kyushu University Hospital, Fukuoka, Japan;4. Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;5. Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan |
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| Abstract: | The prostaglandin (PG) transporter SLCO2A1 regulates PGE2 signaling and interacts with many drugs, and SLCO2A1 defects is associated with PG metabolic disorders. This study aimed to characterize a non-metabolic phenolsulfonphthalein (PSP) transport mediated by SLCO2A1. PSP uptake by HEK293 cells expressing human SLCO2A1 (HEK/2A1 cells) was pH-independent and saturable with a Km value of 54.5 ± 9.5 μM PGE2 competitively inhibited PSP uptake with a Ki of 257.3 ± 22.8 nM. When PSP was intravenously (i.v.) injected, concentration-time curve showed a biphasic response. In Slco2a1-deficient (?/?) mice, AUCinf tented to decrease and the central distribution volume (V1) significantly increased, compared to wild-type (wt) counterparts. Intriguingly, Slco2a1-deficiency significantly reduced a ratio of tissue-to-plasma concentration in the lungs at 15 min after i.v. injection, suggesting that SLCO2A1 limits tissue distribution of PSP. In conclusion, these results prove that PSP is a potential surrogate for monitoring SLCO2A1 function, providing a new concept for diagnostics for the genetic diseases caused by defects in SLCO2A1 gene. |
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