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Antimicrobial Agents and Chemotherapy, July 2004, p. 2604-2609, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2604-2609.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Absorption of Ester Prodrugs in Caco-2 and Rat Intestine Models

Xin He, Mitsuru Sugawara, Yoh Takekuma, and Katsumi Miyazaki*

Department of Pharmacy, Hokkaido University Hospital, Kita-ku, Sapporo 060-8648, Japan

Received 29 November 2003/ Returned for modification 8 February 2004/ Accepted 2 March 2004

The aim of this study was to elucidate the absorption mechanism in Caco-2 and rat intestine models in order to improve the accuracy of prediction of oral absorption of ester prodrugs. Pivampicillin and cefcapene pivoxil hydrochloride (CFPN-PI), ester-type oral antibiotics, were chosen as model ester prodrugs. The level of esterase activity in Caco-2 cells was lower than that measured in the rat jejunum when p-nitrophenyl acetate was used as a substrate. Almost complete ester hydrolysis occurred before the ester prodrugs reached the basolateral side of the monolayer, and the disappearance of prodrugs was thought to be due to metabolism or transport after addition to the apical side of the monolayer. When pivampicillin and CFPN-PI were used, the amounts of ampicillin and cefcapene (CFPN) produced by hydrolysis of prodrugs were increased because intracellular degradation of prodrugs resulted in intracellular accumulation. On the other hand, when ampicillin or CFPN was used, only a small amount of the drug reached the basolateral side of the monolayers and no intracellular accumulation was observed. The permeability of CFPN-PI, the solubility of which is dependent on the acidity of gastric juice, across a Caco-2 monolayer or rat intestine, was also investigated by using an in vitro system that mimics the physiological state of the human gastrointestinal tract. The oral absorption of CFPN-PI in humans is predicted to be good either in the Caco-2 model or in the rat intestine model. It is concluded that our system may be a valuable tool for evaluation of oral absorption of ester prodrugs metabolized during permeation through the intestinal epithelium. Broader evaluation of such a system is warranted.

* Corresponding author. Mailing address: Department of Pharmacy, Hokkaido University Hospital, Kita 14 jo, Nishi 5 chome, Kita-ku, Sapporo 060-8648, Japan. Phone: 81-11-7065680. Fax: 81-11-7561505. E-mail: katsumim{at}med.hokudai.ac.jp.

Antimicrobial Agents and Chemotherapy, July 2004, p. 2604-2609, Vol. 48, No. 7
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.7.2604-2609.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Chanteux, H., Van Bambeke, F., Mingeot-Leclercq, M.-P., Tulkens, P. M. (2005). Accumulation and Oriented Transport of Ampicillin in Caco-2 Cells from Its Pivaloyloxymethylester Prodrug, Pivampicillin. Antimicrob. Agents Chemother. 49: 1279-1288 [Abstract] [Full Text]  


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