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First published on May 20, 2005; DOI: 10.1124/dmd.105.004226

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Received for publication February 14, 2005.
Revised May 18, 2005.
Accepted for publication May 18, 2005.

Identification of esterases expressed in Caco-2 cells and effects of their hydrolyzing activity in predicting human intestinal absorption

Teruko Imai 1*, Masumi Imoto 1, Hisae Sakamoto 1, Mitsuru Hashimoto 1

1 Kumamoto University

* Address correspondence to: E-mail: iteruko{at}gpo.kumamoto-u.ac.jp

Abstract

The absorption characteristics of temocapril were investigated using Caco-2 cells, and the esterases expressed in Caco-2 cells were identified. Temocapril was almost completely hydrolyzed to temocaprilat during transport across Caco-2 cells. Hydrolysis experiments of temocapril in Caco-2 cell 9000g supernatant (S9) and brush border membrane vesicles showed that temocapril was mainly hydrolyzed within the cells after uptake, after which the temocaprilat formed was transported to both the apical and basolateral surfaces. In native PAGE by detection of hydrolase activity for 1-naphthylbutyrate, Caco-2 cell S9 showed a band with high esterase activity and another band with extremely low activity. The proteins in the major and minor bands were identified as carboxylesterase-1 (hCE-1) and carboxylesterase-2 (hCE-2). The abundant expression of hCE-1 in Caco-2 cells was supported by RT-PCR. In the normal human small intestine, hCE-2 is abundantly present, although the human liver expresses much higher levels of hCE-1 and lower levels of hCE-2. The expression pattern of carboxylesterases in Caco-2 cells is completely different from that in human small intestine but quite similar to that in human liver. Since the substrate specificity of hCE-1 differs from that of hCE-2, it is suggested that the prediction of human intestinal absorption using Caco-2 cell monolayers should be performed carefully in the case of ester- and amide-containing drugs such as prodrugs.


Key words: carboxylesterases, cellular transport, drug absorption, intestinal bioavailability, intestinal transport, membrane transport, prodrugs


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