Development of a novel system for estimating human intestinal absorption using Caco-2 cells in the absence of esterase activity

Drug Metabolism and Disposition : the Biological Fate of Chemicals
Kayoko OhuraTeruko Imai

Abstract

Both mRNA and protein levels of the carboxylesterase (CES) isozymes, hCE1 and hCE2, in Caco-2 cells increase in a time-dependent manner, but hCE1 levels are always higher than those of hCE2. In human small intestine, however, the picture is reversed, with hCE2 being the predominant isozyme. Drugs hydrolyzed by hCE1 but not by hCE2 can be hydrolyzed in Caco-2 cells, but they are barely hydrolyzed in human small intestine. The results in Caco-2 cells can be misleading as a predictor of what will happen in human small intestine. In the present study, we proposed a novel method for predicting the absorption of prodrugs in the absence of CES-mediated hydrolysis in Caco-2 cells. The specific inhibition against CES was achieved using bis-p-nitrophenyl phosphate (BNPP). The optimal concentration of BNPP was determined at 200 microM by measuring the transport and hydrolysis of O-butyryl-propranolol (butyryl-PL) as a probe. BNPP concentrations of more than 200 microM inhibited 86% of hydrolysis of butyryl-PL, resulting in an increase in its apparent permeability. Treatment with 200 microM BNPP did not affect paracellular transport, passive diffusion, or carrier-mediated transport. Furthermore, the proposed evaluation system was tested fo...Continue Reading

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Citations

Aug 2, 2002·European Journal of Pharmacology·Rosalind Le FeuvreNancy Rothwell
Aug 27, 2009·Journal of Neuroinflammation·Jessica M CrainJyoti J Watters
Oct 8, 2015·Journal of Pharmaceutical Sciences·Teruko ImaiYuichiro Nakada
May 26, 2012·Journal of Pharmaceutical Sciences·Kayoko OhuraTeruko Imai
Mar 19, 2016·Journal of Natural Products·Rodrigo Moreira da SilvaVeronika Butterweck
Oct 27, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kayoko OhuraTeruko Imai
Mar 4, 2017·Journal of the American Chemical Society·Zhaoqianqi FengBing Xu
Apr 18, 2017·Journal of Pharmaceutical Sciences·Jingjing YuIsabelle Ragueneau-Majlessi
Mar 6, 2019·The Journal of Biological Chemistry·Tatsuya YamazakiSachiko Akashi-Takamura
Apr 9, 2011·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Takaaki Nozawa, Teruko Imai
Nov 12, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Naoki IshiguroOlaf Schaefer
Mar 3, 2020·Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan·Kayoko Ohura
Dec 15, 2019·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Kayoko OhuraTeruko Imai

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