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Xenobiotica
the fate of foreign compounds in biological systems
Volume 44, 2014 - Issue 8
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Xenobiotic Transporters

P-glycoprotein (P-gp)-mediated efflux limits intestinal absorption of the Hsp90 inhibitor SNX-2112 in rats

, , , &
Pages 763-768 | Received 14 Jan 2014, Accepted 04 Feb 2014, Published online: 20 Feb 2014
 

Abstract

1. The promising anticancer agent SNX-2112 (a novel Hsp90 inhibitor) is poorly bioavailable after oral administration. Here, we aim to determine the role of P-glycoprotein (P-gp) in the intestinal absorption of SNX-2112.

2. We found that SNX-2112 significantly stimulated P-gp ATPase activity in in vitro ATPase assay with a small EC50 (the half-maximal effective concentration) value of 0.32 µM.

3. In the single-pass perfused rat intestine model, absorption of SNX-2112 was not favored in the small intestine with a (the wall permeability) value of 0.38–0.64. By contrast, the compound was well absorbed in the colon with a value of 1.19. The P-gp inhibitors cyclosporine and elacridar (i.e. GF120918A) markedly enhanced SNX-2112 absorption in all four intestinal segments (i.e. duodenum, jejunum, ileum and colon) and the fold change ranged from 3.1 to 14.1. Pharmacokinetic study revealed that cyclosporine increased the systemic exposure of SNX-2112 by a 2.5-fold after oral administration.

4. This is the first report that P-gp-mediated efflux is a limiting factor for intestinal absorption of SNX-2112 in rats.

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