1: Pharm Res. 2003 Apr;20(4):624-31.  

Cell handling, membrane-binding properties, and membrane-penetration modeling
approaches of pivampicillin and phthalimidomethylampicillin, two basic esters of
ampicillin, in comparison with chloroquine and azithromycin.

Chanteux H, Paternotte I, Mingeot-Leclercq MP, Brasseur R, Sonveaux E, Tulkens

Unite de pharmacologie cellulaire et moleculaire, Universite Catholique de
Louvain, 73-70, avenue E. Mounier, 73, B-1200 Brussels, Belgium.

PURPOSE: The purpose of this work was to examine and understand the cellular
pharmacokinetics of two basic esters of ampicillin, pivaloyloxymethyl (PIVA) and
phthalimidomethyl (PIMA), in comparison with lysosomotropic drugs (chloroquine,
azithromycin). METHODS: Cell culture studies (J774 macrophages) were undertaken
to study uptake and release kinetics and to assess the influence of
concentration, pH, proton ionophore (monensin), and MRP and P-gp inhibitors
(probenecid, gemfibrozil, cyclosporin A, GF 120918). Equilibrium dialysis with
liposomes were performed to directly asses the extent of drug binding to
bilayers. Conformational analysis modeling of the drug penetration in bilayers
was conducted to rationalize the experimental observations. RESULTS: PIVA and
PIMA showed properties in almost complete contrast with those of chloroquine and
azithromycin, i.e., fast apparent accumulation and fast release at 4 degrees C
as well as at 37 degrees C, saturation of uptake (apparent Kd 40 microM), no
influence of monensin, MRP, or P-gp inhibitors; tight binding to liposomes (Kd
approx. 40 microM); and sharp increase in calculated free energy when forced in
the hydrophobic domain. CONCLUSIONS: Although they are weak organic bases, PIVA
and PIMA show none of the properties of lysosomotropic agents. We hypothesize
that they remain locked onto the pericellular membrane and may never penetrate
cells as such in significant amounts.

PMID: 12739771 [PubMed - in process]