3-(6-isobutyl-9-methoxy-1-4-dioxo-1-2-3-4-6-7-12-12a-octahydropyrazino(1--2--1-6)pyrido(3-4-b)indol-3-yl)propionic-acid-tert-butyl-ester and tolmetin-glycinamide

The purpose of the present study was to investigate the role of efflux transporters on the intestinal absorption of amtolmetin guacyl (MED-15).. The effects of P-glycoprotein (P-gp), multiple resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP) inhibitors on intestinal absorption amount of MED-5 (tolmetin-glycine amide derivative), the metabolite formed from MED-15 in the intestinal epithelial cells were studied in the in vitro everted gut sac experiments. Moreover, the in situ single-pass intestine perfusion was adopted to clarify the role of efflux transporters in excreting MED-5 in knockout mice. The plasma concentration of MED-5 and tolmetin, the metabolite formed from MED-5 was determined in Bcrp1 knockout mice and wild-type mice.. BCRP inhibitor Ko143 (50 μM and 100 μM) significantly increased the intestinal absorption amount in jejunum, ileum and colon (p<0.05). However, no effect was observed in the presence of P-gp inhibitor verapamil and MRP2 inhibitor MK571 in each intestinal segment. Furthermore, the plasma concentration MED-5 and tolmetin, metabolites of MED-15, increased 2-fold and 4-fold, respectively, in Bcrp1 knockout mice compared with wild-type mice after the single-pass perfusion of small intestine with MED-15.. It may be concluded that BCRP plays an important role in the intestinal efflux of MED-5 and limits the bioavailability after oral administration of MED-15.

Topics: Adenosine; Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Biological Availability; Diketopiperazines; Glycine; Heterocyclic Compounds, 4 or More Rings; Intestinal Absorption; Intestinal Mucosa; Leukotriene Antagonists; Male; Mice; Mice, Knockout; Propionates; Pyrroles; Quinolines; Rats; Rats, Sprague-Dawley; Tolmetin; Vasodilator Agents; Verapamil