Determination of absorption characteristics of AG337, a novel thymidylate synthase inhibitor, using a perfused rat intestinal model

Journal of Pharmaceutical Sciences
Ming HuS Roy

Abstract

The purpose of this study was to determine the intestinal absorption characteristics of AG337, a mechanism-based inhibitor of thymidylate synthase, using a perfused rat intestinal model. Effects of site, pH, temperature, concentration, Na+, and inhibitors on the absorption of AG337 were determined, after the compound was shown to be stable in buffers of various pH, blank perfusate, and intestinal homogenate. The results indicated that absorption of AG337 was temperature-, pH-, Na+-, concentration-, and site-dependent. The best site of absorption is duodenum, where the absorption was 3-10 times (p < 0. 05) higher than absorption at jejunum, ileum, and colon. Among the four pH's studied, the best was at pH 6.5 (p < 0.05). Absorption was 80% lower in the absence of Na+, and 75% lower when the temperature of the perfusate was decreased to 4 degreesC. Permeability of AG337 also decreased about 75% when the concentration was raised to 100 microM. These results suggest that a nutrient carrier may be involved in the transport of AG337. To determine the carrier responsible for the absorption of AG337, its absorption was determined in the presence of various inhibitors at different concentrations. The results indicated that transport of ...Continue Reading

References

Jun 1, 1974·The Journal of Clinical Investigation·E Krag, S F Phillips
Jan 1, 1996·Cancer Chemotherapy and Pharmacology·S WebberB V Shetty

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Citations

Nov 25, 2003·The Journal of Alternative and Complementary Medicine : Research on Paradigm, Practice, and Policy·Yong LiuMing Hu
Dec 1, 1999·Pharmaceutical Development and Technology·S RastogiR Suryanarayanan
Jan 31, 2012·Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association·Lan TangZhongqiu Liu
Feb 3, 2011·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yan ChenMing Hu
Feb 27, 2003·The Journal of Pharmacology and Experimental Therapeutics·Jun ChenMing Hu
Sep 16, 2000·Molecular Membrane Biology·H de Koning, G Diallinas
Aug 3, 2006·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Stephen W J WangMing Hu

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