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Identification of Influx Transporter for the Quinolone Antibacterial Agent Levofloxacin

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Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan, and Drug Metabolism & Physicochemistry Research Laboratory, Daiichi Pharmaceutical Co. Ltd., Edogawa-ku, Japan
Cite this: Mol. Pharmaceutics 2007, 4, 1, 85–94
Publication Date (Web):October 24, 2006
https://doi.org/10.1021/mp060082j
Copyright © 2007 American Chemical Society

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    Abstract

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    Quinolone antibacterial agents exhibit high intestinal absorption, selective tissue distribution, and renal and biliary excretion. Several ATP-binding cassette transporters are involved in efflux transport of these agents, but no influx transporters have yet been molecularly identified. In the present study, we aimed to identify the influx transporter(s) of quinolone antibiotics using levofloxacin as a model compound. Several candidate transporter genes were selected based on differential expression of mRNAs among Caco-2 cell subclones that exhibited differential uptake activities for levofloxacin. Based on a functional analysis of each transporter gene for which a good correlation was found between expression level and levofloxacin transport activity in the Caco-2 subclones, organic anion transporting polypeptide 1A2 (OATP1A2 (OATP-A), SLCO1A2) was concluded to transport levofloxacin. When OATP1A2 was expressed in Xenopus oocytes, levofloxacin transport was essentially pH-independent and was not stereoselective. OATP1A2-mediated uptake of levofloxacin showed a Km value of 136 μM. Apparent uptake of levofloxacin by Caco-2 cells showed high- and low-affinity components with Km values of 0.489 and 14.6 mM, respectively. Accordingly, plural transporters are functional for the transport of levofloxacin in Caco-2 cells, and OATP1A2 is likely to function as a high-affinity transporter. The inhibitory effects and the expression of transport activity of other quinolone antibacterial agents suggested that OATP1A2 commonly transports all the agents tested. In conclusion, this is the first identification of an influx transporter for fluoroquinolones, and the results suggest that active influx transport at least partially explains the high membrane permeability of the quinolone agents in various tissues.

    Keywords: Fluoroquinolone; transporter; OATP; absorption; intestine; levofloxacin; Caco-2 cell

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     Tokyo University of Science.

     Daiichi Pharmaceutical Co. Ltd.

    *

     To whom correspondence should be addressed. Department of Molecular Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamasaki, Noda, Chiba 278-8510, Japan. Tel/fax:  +81-4-7121-3615. E-mail:  [email protected].

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