Abstract
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.
Footnotes
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This study was supported by grants-in-aid for scientific research (A) (KAKENHI 17209005 for Y.S.) and by grants-in-aid for scientific research (B) (KAKENHI 18390046 for H.K.) from Japan Society for the Promotion of Science.
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doi:10.1124/dmd.107.014969.
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ABBREVIATIONS: MRP (Mrp), multidrug resistance-associated protein; EHBR, Eisai hyperbilirubinemic rat; P-gp, P-glycoprotein; UFX, ulifloxacin; GPFX, grepafloxacin; BCRP (Bcrp), breast cancer resistance protein; CPFX, ciprofloxacin; OFX, ofloxacin; Ko143, 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; MDCK, Madin-Darby canine kidney; GFP, green fluorescent protein; h, human; m, mouse; LC, liquid chromatography; MS, mass spectrometry; BSP, sulfobromophthalein; BBB, blood-brain barrier.
- Received January 23, 2007.
- Accepted July 12, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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