Xiao Yunpeng, Deng Jifeng, Liu Xiaoxiao, Huang Jiujiu, Sun Yongxue, Dai Renke, Hong Mei
College of Life Science and Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms (Y.X., X.L., J.H., M.H.) and College of Veterinary Medicine (Y.S.), South China Agricultural University, Guangzhou, China; and School of Bioscience & Bioengineering, South China University of Technology, Guangzhou, China (J.D., R.D.).
College of Life Science and Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms (Y.X., X.L., J.H., M.H.) and College of Veterinary Medicine (Y.S.), South China Agricultural University, Guangzhou, China; and School of Bioscience & Bioengineering, South China University of Technology, Guangzhou, China (J.D., R.D.)
Drug Metab Dispos. 2014 Aug;42(8):1261-7. doi: 10.1124/dmd.114.057448. Epub 2014 Jun 2.
Because of their wide distribution and capability of transporting a large variety of compounds, organic anion-transporting polypeptides (OATPs) have been extensively recognized as crucial players in absorption, distribution, and excretion of various drugs. OATP1A2 was the first cloned human OATP and has been found to transport wide range of endogenous and exogenous compounds. Bovine Oatp1a2 (bOatp1a2) shares high homology with human OATP1A2 and is considered the functional ortholog of the latter. Previous study in our laboratory demonstrated that bOatp1a2 transport of estrone-3-sulfate (ES) exhibited biphasic saturation kinetics. In the present study, we investigated the transport function of bOatp1a2 for four different quinolone antibacterial agents (enrofloxacin, levofloxacin, norfloxacin, and ciprofloxacin) and found that all the tested fluoroquinolones can be transported by bOatp1a2. Further studies showed that different binding sites are responsible for the transport of different fluoroquinolones. Both ciprofloxacin and norfloxacin exhibited biphasic saturation kinetics. The Kms of the high- and low-affinity components for ciprofloxacin were 3.80 ± 0.85 μM and 182 ± 31 μM, respectively, while those for norfloxacin were 24.7 ± 0.1 μM and 393 ± 79 μM, respectively. Enrofloxacin and levofloxacin showed an inhibitory effect on the uptake of only the high concentration of ES and thus may be transported by the low-affinity site for ES. Interestingly, enrofloxacin and levofloxacin demonstrated an activation effect on ES uptake at the high-affinity binding site. These results suggested that multiple binding sites within the structure of bOatp1a2 may be responsible for the uptake of different quinolone antimicrobial agents.
由于有机阴离子转运多肽（OATPs）分布广泛且能够转运多种化合物，它们已被广泛认为是各种药物吸收、分布和排泄的关键参与者。OATP1A2是首个被克隆的人类OATP，已发现它能转运多种内源性和外源性化合物。牛Oatp1a2（bOatp1a2）与人类OATP1A2具有高度同源性，被认为是后者的功能同源物。我们实验室之前的研究表明，bOatp1a2对硫酸雌酮（ES）的转运表现出双相饱和动力学。在本研究中，我们研究了bOatp1a2对四种不同喹诺酮类抗菌药物（恩诺沙星、左氧氟沙星、诺氟沙星和环丙沙星）的转运功能，发现所有测试的氟喹诺酮类药物都能被bOatp1a2转运。进一步研究表明，不同的结合位点负责不同氟喹诺酮类药物的转运。环丙沙星和诺氟沙星均表现出双相饱和动力学。环丙沙星高亲和力和低亲和力成分的Km值分别为3.80±0.85μM和182±31μM，而诺氟沙星的Km值分别为24.7±0.1μM和393±79μM。恩诺沙星和左氧氟沙星仅对高浓度ES的摄取有抑制作用，因此可能通过ES的低亲和力位点转运。有趣的是，恩诺沙星和左氧氟沙星在高亲和力结合位点对ES摄取表现出激活作用。这些结果表明，bOatp1a2结构内的多个结合位点可能负责不同喹诺酮类抗菌药物的摄取。
