16/05/2009 1 ECCMID 2009 O23 - Pharmacokinetics/Pharmacodynamics: Clinical relevance Competition between Ciprofloxacin and Antiviral Agents ( Adefovir, Saquinavir, Ritonavir) for Efflux Transporters in J774 Macrophages L. Garcia*, B. Marquez, S. Carryn, M.P. Mingeot-Leclercq, P.M. Tulkens, F. Van Bambeke Unité de Pharmacologie Cellulaire et Moléculaire Louvain Drug Research Institute Université Catholique de Louvain <www.facm.ucl.ac.be>
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Competition between Ciprofloxacin and Antiviral Agents … · 2009-05-19 · and Antiviral Agents (Adefovir, Saquinavir, Ritonavir) for Efflux Transporters in J774 Macrophages L.
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The CIPRO-resistant cellsoverexpress Mrp2 and Mrp4,
but Mrp4 predominates
Marquez et al. AAC (2009) [Epub ahead of print]
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Aim of our study
The aim of our work is to examine, in wild-type and Ciprofloxacin-resistant macrophages, the potential competition between Ciprofloxacin and preferential
substrates of Mrp2 and Mrp4 in order to better identify and further
characterize the Fluoroquinolone transporter.
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Adefovir and MRP4PMEA
9-(2-PhosphonylMethoxyEthyl)Adenine
Reid et al. Mol Pharmacol. 2003 63:1094-103Imaoka et al. Mol Pharmacol. 2007 71:619-27.
Saquinavir and MRP2
Ritonavir and MRP2
N
C
O
O-
O
HN
N
F
CIPROFLOXACIN
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Bis(POM)PMEA
Mono(POM)PMEA
PMEA
9-[2-(BisPivaloyolOxyMethyl)PhosphoMEthoxy]Adenine[Bis(POM)PMEA or Adefovir Dipivoxil]
Hydrolysis of Bis(POM)PMEA
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Measure of cellular content in CIP
CIP 50 µM
Bis(POM)PMEA300 µM
Wild-Type Cells CIP-Resistant Cells
Competition between CIP and Bis(POM)PMEA
Fluorimetry: λ
excitation = 275 nm; λ
emission = 450 nm
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Accumulation of Ciprofloxacin
The accumulation of CIP is increased in the presence of Gemfibrozil or Bis(POM)PMEA in both cell types