Evaluation of intestinal absorption of amtolmetin guacyl in rats: breast cancer resistant protein as a primary barrier of oral bioavailability.

Abstract

AIMS:

The purpose of the present study was to investigate the role of efflux transporters on the intestinal absorption of amtolmetin guacyl (MED-15).

MAIN METHODS:

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.

KEY FINDINGS:

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.

SIGNIFICANCE:

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.

• Authors: Zhihui Rong, Yanjiao Xu, Chengliang Zhang, Daochun Xiang, Xiping Li, Dong Liu
• Journal: Life sciences (Life Sci) Vol. 92 Issue 3 Pg. 245-51 (Feb 27 2013) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 23333829 (Publication Type: Journal Article)
• Copyright: Copyright © 2013. Published by Elsevier Inc.

Chemical References

• 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
• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Abcc2 protein, rat
• Abcg2 protein, mouse
• Abcg2 protein, rat
• Anti-Inflammatory Agents, Non-Steroidal
• Diketopiperazines
• Heterocyclic Compounds, 4 or More Rings
• Leukotriene Antagonists
• Propionates
• Pyrroles
• Quinolines
• Vasodilator Agents
• ST 679
• verlukast
• tolmetin glycinamide
• Verapamil
• Tolmetin
• Adenosine
• Glycine

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, genetics, metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (antagonists & inhibitors, genetics, metabolism)
• Adenosine (analogs & derivatives, pharmacology)
• Administration, Oral
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacokinetics, pharmacology)
• Biological Availability
• Diketopiperazines
• Glycine (analogs & derivatives, pharmacokinetics, pharmacology)
• Heterocyclic Compounds, 4 or More Rings
• Intestinal Absorption (drug effects, genetics)
• Intestinal Mucosa (metabolism)
• Leukotriene Antagonists (pharmacology)
• Male
• Mice
• Mice, Knockout
• Propionates (pharmacology)
• Pyrroles (pharmacokinetics, pharmacology)
• Quinolines (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Tolmetin (analogs & derivatives, pharmacology)
• Vasodilator Agents (pharmacology)
• Verapamil (pharmacology)