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First published on January 24, 2006; DOI: 10.1124/dmd.105.008219

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Received for publication November 8, 2005.
Revised December 20, 2005.
Accepted for publication January 20, 2006.

Breast Cancer Resistance Protein (BCRP/ABCG2) transports fluoroquinolone antibiotics and affects their oral availability, pharmacokinetics and milk secretion

Gracia Merino 1, Ana I. Alvarez 1, Mivis M. Pulido 1, Antonio J. Molina 1, Alfred H. Schinkel 2, Julio G. Prieto 1*

1 University of Leon 2 The Netherlands Cancer Institute

* Address correspondence to: E-mail: dfijpf{at}unileon.es

Abstract

The Breast Cancer Resistance Protein (BCRP/ABCG2) is an ATP binding cassette drug efflux transporter that extrudes xenotoxins from cells in intestine, liver, mammary gland and other organs, affecting the pharmacological and toxicological behavior of many compounds, including their secretion into the milk. The purpose of this study was to determine whether three widely used fluoroquinolone antibiotics (ciprofloxacin, ofloxacin and norfloxacin) are substrates of Bcrp1/BCRP and to investigate the possible role of this transporter in the in vivo pharmacokinetic profile of these compounds and their secretion into the milk. Using polarized cell lines, we found that ciprofloxacin, ofloxacin and norfloxacin are transported by mouse Bcrp1 and human BCRP. In vivo pharmacokinetic studies showed that ciprofloxacin plasma concentration was more than 2-fold increased in Bcrp1-/- compared to wild-type mice (1.77 ± 0.73 versus 0.85 ± 0.39 µg/ml, p < 0.01) after oral administration of ciprofloxacin (10 mg/kg). The AUC in Bcrp1-/- mice was 1.5-fold higher than that in wild-type mice (48.63 ± 5.66 versus 33.10 ± 4.68 min.µg/ml, p < 0.05) after i.v. administration (10 mg/kg). The milk concentration and milk to plasma ratio of ciprofloxacin was 2-fold higher in wild-type compared to Bcrp1-/- lactating mice. We conclude that Bcrp1 is one of the determinants for the bioavailability of fluoroquinolones and their secretion into the milk.


Key words: ABC transporters, active transport, antibiotics, drug disposition, drug efflux, drug secretion, drug transport, membrane transport, pharmacokinetics, transporters


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