Received for publication January 23, 2007.
Revised July 10, 2007.
Accepted for publication July 12, 2007.

Involvement of Breast Cancer Resistance Protein (ABCG2) in the biliary excretion mechanism of fluoroquinolones

Abstract

Fluoroquinolones are one of the 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 (grepafloxaxcin, ulifloxacin, ciprofloxacin and ofloxacin). In MDCK II 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, Ko143. Plasma and bile concentrations of fluoroquinolones were determined in wild type and Bcrp (-/-) mice following intravenous bolus injection. The cumulative biliary excretion of fluoroquinolones was significantly reduced in Bcrp (-/-) mice, resulting in a reduction of the biliary excretion clearances to 50, 16, 40 and 36% 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-to-plasma concentration ratios of fluoroquinolones in the liver or brain, while 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.

Key words: ABC transporters, drug clearance, drug transport, hepatobiliary transport, membrane transport