1: Antimicrob Agents Chemother. 2005 Apr;49(4):1279-88. 

Accumulation and oriented transport of ampicillin in caco-2 cells from its
pivaloyloxymethylester prodrug, pivampicillin.

Chanteux H, Van Bambeke F, Mingeot-Leclercq MP, Tulkens PM.

Unite de pharmacologie cellulaire et moleculaire, UCL 73-70, Avenue E. Mounier,
73, B-1200 Brussels, Belgium. tulkens@facm.ucl.ac.be.

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

PMID: 15793098 [PubMed - in process]