Involvement of Multidrug Resistance-Associated Protein 2 in Intestinal Secretion of Grepafloxacin in Rats

Abstract

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.

Differential Roles of P-Glycoprotein, Multidrug Resistance-Associated Protein 2, and CYP3A on Saquinavir Oral Absorption in Sprague-Dawley Rats

“…MRP2/ Mrp2 appears to play a minor role in intestinal absorption and secretion, especially when Pgp is involved even though they have similar intestinal localization. Furthermore, the oral absorption of grepafloxacin, a Mrp2 and Pgp substrate, was not significantly enhanced by the inhibition of Mrp2; however, biliary excretion was significantly reduced, suggesting differential roles for Pgp and Mrp2 in the intestine and liver (Naruhashi et al, 2002).…”

Hepatic and Intestinal Multidrug Resistance-Associated Protein 2: Transcriptional and Post-transcriptional Regulation by Xenobiotics

“…Probenecid is a classical competitive inhibitor of organic anions transport also used in the clinical practice to enhance plasma levels of antibiotics. Although nonspeciic, its inhibitory efect on intestinal MRP2 was clearly demonstrated in rats [95] and in Caco-2 cells [90]. Nowadays, more potent and speciic MRP inhibitors like MK5 1 are preferred for characterization of transport speciicity.…”

Involvement of Multidrug Resistance-Associated Protein 1 in Intestinal Toxicity of Methotrexate

“…play a key role in drug absorption (7,8,(13)(14)(15)(16), little is known about the pharmacological and/or toxicological effects of transporter(s) expressed in undifferentiated cells in the small intestine. The aim of the present study is to clarify whether Mrp1, which was reported to be expressed in proliferative cells of crypts in mice, is involved in the intestinal toxicity provoked by MTX in vivo.…”

“…For example, P-glycoprotein (P-gp/ABCB1) and Mrp2 limit the oral bioavailability of certain ß-blockers and new quinolone antibiotics by extruding these drugs into the intestinal tract (13,14). Both Mrp2 and Mrp3/Abcc3 are expressed in the small intestine, and accept MTX as a substrate (15,16).…”