Role of intestinal efflux transporters in the intestinal absorption of methotrexate in rats.
The role of intestinal efflux transporters such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs) in intestinal absorption of methotrexate was examined in rats. In everted intestine, the mucosal efflux of methotrexate after application to serosal side was higher in jejunum than ileum, and the efflux in jejunum was suppressed by pantoprazole, a BCRP inhibitor, and probenecid, an MRP inhibitor, but not by verapamil, a P-gp inhibitor. The mucosal methotrexate efflux in ileum was suppressed by pantoprazole, but not by other inhibitors. On the other hand, the serosal efflux of methotrexate after application to mucosal side was greater in ileum than jejunum, and was suppressed by probenecid. In in-vivo rat studies, the intestinal absorption of methotrexate was significantly higher when methotrexate was administered to ileum than jejunum. Pantoprazole increased methotrexate absorption from jejunum and ileum. Probenecid increased the absorption of methotrexate from jejunum but decreased the absorption from ileum, as evaluated by peak plasma methotrexate levels. In conclusion, BCRP and MRPs are involved in the regional difference in absorption of methotrexate along the intestine, depending on their expression sites.
Yokooji
Tomoharu
T
Department of Pharmaceutics and Therapeutics, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Murakami
Teruo
T
Yumoto
Ryoko
R
Nagai
Junya
J
Takano
Mikihisa
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D001692:Biological Transport; D015153:Blotting, Western; D015870:Gene Expression; D007082:Ileum / Q000378:metabolism; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C116614:ABCG2 protein, human