QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.107.014969v1 35/10/1873    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ando, T. Articles by Sugiyama, Y. Search for Related Content PubMed PubMed Citation Articles by Ando, T. Articles by Sugiyama, Y.

Involvement of Breast Cancer Resistance Protein (ABCG2) in the Biliary Excretion Mechanism of Fluoroquinolones

Graduate School of Pharmaceutical Sciences, the University of Tokyo, Tokyo, Japan (T.A., H.K., Y.S.); Faculty of Veterinary Medicine, University of León, León, Spain (G.M., A.I.A.); and Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands (A.H.S.)

Fluoroquinolones are effective antibiotics for the treatment of bile duct infections. It has been shown that the biliary excretion of grepafloxacin is partly accounted for by multidrug resistance-associated protein 2 (MRP2/ABCC2), whereas neither MRP2 nor P-glycoprotein is involved in the biliary excretion of ulifloxacin. In the present study, we examined the involvement of breast cancer resistance protein (BCRP/ABCG2) in the biliary excretion of fluoroquinolones (grepafloxacin, ulifloxacin, ciprofloxacin, and ofloxacin). In Madin-Darby canine kidney II cells expressing human BCRP or mouse Bcrp, the basal-to-apical transport of grepafloxacin and ulifloxacin was greater than that of the mock control, which was inhibited by a BCRP inhibitor, 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indol-3-yl)-propionic acid tert-butyl ester (Ko143). Plasma and bile concentrations of fluoroquinolones were determined in wild-type and Bcrp(-/-) mice after i.v. bolus injection. The cumulative biliary excretion of fluoroquinolones was significantly reduced in Bcrp(-/-) mice, resulting in a reduction of the biliary excretion clearances to 86, 50, 40, and 16 of the control values, for ciprofloxacin, grepafloxacin, ofloxacin, and ulifloxacin, respectively. Preinfusion of sulfobromophthalein significantly inhibited the biliary excretion of grepafloxacin in Bcrp(-/-) mice. There was no change in the tissue/plasma concentration ratios of fluoroquinolones in the liver or brain, whereas those in the kidney were increased 3.6- and 1.5-fold for ciprofloxacin and grepafloxacin, respectively, in Bcrp(-/-) mice but were unchanged for ofloxacin and ulifloxacin. The present study shows that BCRP mediates the biliary excretion of fluoroquinolones and suggests that it is also involved in the tubular secretion of ciprofloxacin and grepafloxacin.

This article has been cited by other articles:

				K. He, M. W. Lago, R. A. Iyer, W.-C. Shyu, W. G. Humphreys, and L. J. Christopher Lacteal Secretion, Fetal and Maternal Tissue Distribution of Dasatinib in Rats Drug Metab. Dispos., December 1, 2008; 36(12): 2564 - 2570. [Abstract] [Full Text] [PDF]

				H. Fukuda, R. Ohashi, M. Tsuda-Tsukimoto, and I. Tamai Effect of Plasma Protein Binding on in Vitro-in Vivo Correlation of Biliary Excretion of Drugs Evaluated by Sandwich-Cultured Rat Hepatocytes Drug Metab. Dispos., July 1, 2008; 36(7): 1275 - 1282. [Abstract] [Full Text] [PDF]

				J. Enokizono, H. Kusuhara, A. Ose, A. H. Schinkel, and Y. Sugiyama Quantitative Investigation of the Role of Breast Cancer Resistance Protein (Bcrp/Abcg2) in Limiting Brain and Testis Penetration of Xenobiotic Compounds Drug Metab. Dispos., June 1, 2008; 36(6): 995 - 1002. [Abstract] [Full Text] [PDF]