Ando Tomohiro, Kusuhara Hiroyuki, Merino Gracia, Alvarez Ana I, Schinkel Alfred H, Sugiyama Yuichi
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Drug Metab Dispos. 2007 Oct;35(10):1873-9. doi: 10.1124/dmd.107.014969. Epub 2007 Jul 16.
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.
氟喹诺酮类是治疗胆管感染的有效抗生素。已表明格帕沙星的胆汁排泄部分由多药耐药相关蛋白2（MRP2/ABCC2）介导，而乌利沙星的胆汁排泄既不涉及MRP2也不涉及P-糖蛋白。在本研究中，我们研究了乳腺癌耐药蛋白（BCRP/ABCG2）在氟喹诺酮类（格帕沙星、乌利沙星、环丙沙星和氧氟沙星）胆汁排泄中的作用。在表达人BCRP或小鼠Bcrp的Madin-Darby犬肾II细胞中，格帕沙星和乌利沙星从基底到顶端的转运大于mock对照，这被BCRP抑制剂3-(6-异丁基-9-甲氧基-1,4-二氧代-1,2,3,4,6,7,12,12a-八氢吡嗪并[1',2':1,6]吡啶并[3,4-b]吲哚-3-基)-丙酸叔丁酯（Ko143）抑制。静脉推注后，测定野生型和Bcrp(-/-)小鼠血浆和胆汁中氟喹诺酮类的浓度。Bcrp(-/-)小鼠中氟喹诺酮类的累积胆汁排泄显著减少，导致环丙沙星、格帕沙星、氧氟沙星和乌利沙星的胆汁排泄清除率分别降至对照值的86%、50%、40%和16%。预先注入磺溴酞钠显著抑制Bcrp(-/-)小鼠中格帕沙星的胆汁排泄。肝或脑中氟喹诺酮类的组织/血浆浓度比没有变化，而在Bcrp(-/-)小鼠中，肾中环丙沙星和格帕沙星的组织/血浆浓度比分别增加了3.6倍和1.5倍，而氧氟沙星和乌利沙星的则没有变化。本研究表明BCRP介导氟喹诺酮类的胆汁排泄，并提示其也参与环丙沙星和格帕沙星的肾小管分泌。
