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

• Published in: Drug metabolism and disposition Vol. 35; no. 10; pp. 1873 - 1879
• Main Authors: ANDO, Tomohiro, KUSUHARA, Hiroyuki, MERINO, Gracia, ALVAREZ, Ana I, SCHINKEL, Alfred H, SUGIYAMA, Yuichi
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01-10-2007
• Subjects: Animals; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Bile - metabolism; Biological and medical sciences; Brain - metabolism; Cell Line; Dogs; Fluoroquinolones - blood; Fluoroquinolones - pharmacokinetics; Kidney - metabolism; Liver - metabolism; Male; Medical sciences; Mice; Mice, Inbred Strains; Mice, Knockout; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Pharmacology. Drug treatments; Sulfobromophthalein - pharmacology; Biliary tract; ABCG2 gene; Excretion; Fluoroquinolone derivatives; Treatment resistance; Digestive system; Pharmacokinetics; Antibacterial agent; Mechanism of action; ABC transporter; Breast cancer resistance protein
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.107.014969

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-1,2,3,4,6,7,12,12 a -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.