Active intestinal absorption of fluoroquinolone antibacterial agent ciprofloxacin by organic anion transporting polypeptide, Oatp1a5
Active intestinal absorption of fluoroquinolone antibacterial agent ciprofloxacin by organic anion transporting polypeptide, Oatp1a5
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DOI：
10.1002/bdd.1809
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发表时间：
2012-09-01
影响因子：
2.1
通讯作者：
Tamai, Ikumi
中科院分区：
文献类型：
--
作者：
Arakawa, Hiroshi;Shirasaka, Yoshiyuki;Tamai, Ikumi
氟喹诺酮类抗菌药物尽管具有亲水性，但在口服给药后被有效吸收，这意味着在其膜转运过程中涉及载体介导的转运。几种氟喹诺酮类药物是人肠源性Caco-2细胞中表达的有机阴离子转运蛋白多肽OATP 1A 2的底物。在本研究中，为了阐明OATP参与环丙沙星的肠吸收，Oatp 1a 5，这是在大鼠肠上皮细胞的顶端膜表达，环丙沙星的肠吸收的贡献进行了研究。用原位法和血管灌流闭环法测定了环丙沙星的肠膜通透性。在存在乳腺癌耐药蛋白抑制剂7，8-苯甲酮和P-糖蛋白抑制剂伊维菌素的情况下，环丙沙星从肠腔中消失和吸收的量显著增加，而在这些抑制剂与Oatp 1a 5抑制剂柚皮苷组合的情况下，环丙沙星从肠腔中消失和吸收的量显著降低。此外，Oatp 1a 5介导的摄取环丙沙星是饱和的Km值为140？μ m，柚苷抑制的IC 50值为18？μ m的非洲爪蟾卵母细胞表达Oatp 1a 5。柚皮苷降低了环丙沙星从粘膜到浆膜侧的渗透，IC 50值为7.5？μ m的Ussing型腔室方法。IC 50估计值与Oatp 1a 5相当。这些数据表明，Oatp 1a 5是环丙沙星的肠道吸收的部分原因。结论：Oatp 1a 5等内流转运蛋白和P-gp、Bcrp等外排转运蛋白均能影响环丙沙星的肠吸收。版权所有（c）2012约翰威利父子有限公司
Fluoroquinolone antimicrobial drugs are absorbed efficiently after oral administration despite of their hydrophilic nature, implying an involvement of carrier-mediated transport in their membrane transport process. It has been that several fluoroquinolones are substrates of organic anion transporter polypeptides OATP1A2 expressed in human intestine derived Caco-2 cells. In the present study, to clarify the involvement of OATP in intestinal absorption of ciprofloxacin, the contribution of Oatp1a5, which is expressed at the apical membranes of rat enterocytes, to intestinal absorption of ciprofloxacin was investigated in rats. The intestinal membrane permeability of ciprofloxacin was measured by in situ and the vascular perfused closed loop methods. The disappeared and absorbed amount of ciprofloxacin from the intestinal lumen were increased markedly in the presence of 7,8-benzoflavone, a breast cancer resistance protein inhibitor, and ivermectin, a P-glycoprotein inhibitor, while it was decreased significantly in the presence of these inhibitors in combination with naringin, an Oatp1a5 inhibitor. Furthermore, the Oatp1a5-mediated uptake of ciprofloxacin was saturable with a Km value of 140?mu m, and naringin inhibited the uptake with an IC50 value of 18? mu m by Xenopus oocytes expressing Oatp1a5. Naringin reduced the permeation of ciprofloxacin from the mucosal-to-serosal side, with an IC50 value of 7.5?mu m by the Ussing-type chamber method. The estimated IC50 values were comparable to that of Oatp1a5. These data suggest that Oatp1a5 is partially responsible for the intestinal absorption of ciprofloxacin. In conclusion, the intestinal absorption of ciprofloxacin could be affected by influx transporters such as Oatp1a5 as well as the efflux transporters such as P-gp and Bcrp. Copyright (c) 2012 John Wiley & Sons, Ltd.