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

Authors: Rong, Z  Xu, Y  Zhang, C  Xiang, D  Li, X  Liu, D 
Citation: Rong Z, etal., Life Sci. 2013 Feb 27;92(3):245-51. doi: 10.1016/j.lfs.2012.12.010. Epub 2013 Jan 16.
Pubmed: (View Article at PubMed) PMID:23333829
DOI: Full-text: DOI:10.1016/j.lfs.2012.12.010

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 muM and 100 muM) 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.


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RGD Object Information
RGD ID: 11099975
Created: 2016-06-09
Species: All species
Last Modified: 2016-06-09
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.