Involvement of multidrug resistance-associated protein 2 in intestinal secretion of grepafloxacin in rats.
We investigated the contribution of multidrug resistance-associated protein 2 (MRP2) to the secretory transport of grepafloxacin and compared its functional role with that of P-glycoprotein (P-gp) by using Sprague-Dawley rats (SDRs) and Eisai hyperbilirubinemic rats (EHBRs), in which MRP2 is hereditarily defective. In intestinal tissue from SDRs mounted in Ussing chambers, the level of transport in the direction from the serosal layer to the mucosal layer was twofold greater than that in the direction from the mucosal layer to the serosal layer. This secretory transport of grepafloxacin was diminished by both probenecid, an MRP2 inhibitor, and cyclosporine, a P-gp inhibitor. In intestinal tissue from EHBRs, the secretory transport of grepafloxacin was lower than that in intestinal tissue from SDRs and was inhibited by cyclosporine but not by probenecid. The absorption of grepafloxacin from intestinal loops in SDRs was in the order of duodenum > jejunum > ileum and was increased by cyclosporine but not by probenecid. The absorption in EHBRs was not higher than that in SDRs. The intestinal secretory clearance in SDRs after intravenous administration of grepafloxacin was shown to be greater for the ileum than for the duodenum, which is in good agreement with the previously reported regional expression profile of MRP2 mRNA. The intestinal secretory clearance was lower in EHBRs than in SDRs. Accordingly, in addition to P-gp, MRP2 might play a role in the secretory transport of grepafloxacin. The function of MRP2 in facilitating grepafloxacin transport in the secretory direction is more pronounced both in vitro and in vivo, while the restriction of entry from the lumen into the cell by MRP2 seems to be negligible, compared with that by P-gp, in the case of grepafloxacin.
Naruhashi
Kazumasa
K
Faculty of Pharmaceutical Sciences Kanazawa University, Kanazawa 920-0934. CREST, Japan.
Tamai
Ikumi
I
Inoue
Natsuko
N
Muraoka
Hiromi
H
Sai
Yoshimichi
Y
Suzuki
Nagao
N
Tsuji
Akira
A
D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics*; D001659:Biliary Tract / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000502:physiology*; D024841:Fluoroquinolones; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism*; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D010879:Piperazines / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010879:Piperazines; C075375:grepafloxacin