Functional Pleiotropy of Organic Anion Transporting Polypeptide OATP2B1 Due to Multiple Binding Sites

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著者

    • SHIRASAKA Yoshiyuki
    • Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
    • MORI Takanori
    • Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
    • SHICHIRI Megumi
    • Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
    • NAKANISHI Takeo
    • Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University
    • TAMAI Ikumi
    • Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University

抄録

  The purpose of this study was to examine whether the presence of multiple binding sites can explain the pleiotropy of substrate recognition by OATP2B1, using <i>Xenopus</i> oocytes expressing OATP2B1. OATP2B1-mediated uptake of estrone-3-sulfate apparently exhibited biphasic saturation kinetics, with <i>K</i><sub>m</sub> values of 0.10 ± 0.05 and 29.9 ± 12.1 µM and <i>V</i><sub>max</sub> values of 14.1 ± 6.4 and 995 ± 273 fmol/min/oocyte for high- and low-affinity sites, respectively. Contribution analysis revealed that transport of estrone-3-sulfate mediated by high- and low-affinity sites on OATP2B1 could be evaluated at the concentrations of 0.005 and 50 µM, respectively. pH-dependence study of OATP2B1-mediated estrone-3-sulfate uptake suggested that high- and low-affinity sites show different pH sensitivity. When the inhibitory effect of 12 compounds on estrone-3-sulfate uptake by high- and low-affinity sites on OATP2B1 was examined, 4 compounds appeared to be inhibitors of the high-affinity site on OATP2B1. Two other compounds appeared to be inhibitors for the low-affinity site and four others were inhibitory at both sites. These results indicated the presence of multiple binding sites on OATP2B1 with different affinity for drugs. Accordingly, it is likely that drug-drug and drug-beverage interactions occur only when two drugs share the same binding site on OATP2B1.<br>

収録刊行物

  • 薬物動態

    薬物動態 27(3), 360-364, 2012

    日本薬物動態学会

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