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Antimicrobial Agents and Chemotherapy, April 2005, p. 1279-1288, Vol. 49, No. 4
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.4.1279-1288.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Accumulation and Oriented Transport of Ampicillin in Caco-2 Cells from Its Pivaloyloxymethylester Prodrug, Pivampicillin

Hugues Chanteux,{dagger} Françoise Van Bambeke, Marie-Paule Mingeot-Leclercq, and Paul M. Tulkens*

Unité de pharmacologie cellulaire et moléculaire, Université catholique de Louvain, Brussels, Belgium

Received 2 June 2004/ Returned for modification 3 August 2004/ Accepted 17 November 2004

Pivampicillin (PIVA), an acyloxymethylester of ampicillin, is thought to enhance the oral bioavailability of ampicillin because of its greater lipophilicity compared to that of ampicillin. The fate of PIVA in intestinal cells and the exact location of its conversion into ampicillin have, however, never been unambiguously established. Polarized Caco-2 cells have been used to examine the handling of PIVA and the release of ampicillin from PIVA by the intestinal epithelium. Experiments were limited to 3 h. Cells incubated with PIVA (apical pole) showed a fast accumulation of ampicillin and transport toward the basolateral medium, whereas PIVA itself was only poorly accumulated and transported. Cells incubated with free ampicillin accumulated and transported only minimal amounts of this drug. Release of ampicillin from cells incubated with PIVA was unaffected by PEPT1 and OCTN2 inhibitors but was sharply decreased after ATP depletion or addition of bis(4-nitrophenyl)-phosphate (BNPP; an esterase inhibitor). PIVA incubated with Caco-2 lysates released free ampicillin, and this release was inhibited by BNPP. Efflux studies showed that the ampicillin that accumulated in cells after incubation with PIVA was preferentially transported out of the cells through the basolateral pole. This efflux was decreased by multidrug resistance-associated protein (MRP) inhibitors (probenecid, MK-571) and by ATP depletion. A phthalimidomethylester of ampicillin that resists cellular esterases failed to cause any significant release (cell lysate) or transport (polarized Caco-2 cells) of ampicillin. These results show that when PIVA is given to Caco-2 cells from their apical pole, ampicillin is released intracellularly and that ampicillin is thereafter preferentially effluxed into the basolateral medium through an MRP-like transporter.

* Corresponding author. Mailing address: Unité de pharmacologie cellulaire et moléculaire, UCL 73-70, Avenue E. Mounier, 73, B-1200 Brussels, Belgium. Phone: 32-2-7647371. Fax: 32-2-7647373. E-mail: tulkens{at}facm.ucl.ac.be.

{dagger} Present address: Unité de microbiologie, Université catholique de Louvain, B-1200 Brussels, Belgium.

Antimicrobial Agents and Chemotherapy, April 2005, p. 1279-1288, Vol. 49, No. 4
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.4.1279-1288.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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