Kinetic characterization of secretory transport of a new ciprofloxacin derivative (CNV97100) across Caco-2 cell monolayers.
Kinetic characterization of secretory transport of a new ciprofloxacin derivative (CNV97100) across Caco-2 cell monolayers.
复制标题
新型环丙沙星衍生物 (CNV97100) 跨 Caco-2 细胞单层分泌转运的动力学表征。
DOI：
10.1002/jps.10244
复制
发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Hu,Ming
中科院分区：
文献类型：
--
作者：
Ruiz-Garcia,Ana;Lin,Huimin;Pla-Delfina,JoseM;Hu,Ming
利用Caco-2细胞培养模型研究了新型氟喹诺酮类抗生素CNV 97100及其类似物的转运动力学。这些类似物的单向渗透性大于环丙沙星（p< 0.05）。4′-N-取代的类似物（CNV 97101 -104）的吸收渗透性（PAB）比未取代的类似物高400-600%，而分泌渗透性（PBA）比未取代的类似物高25-80%，因为CNV 97101 -104是外排转运蛋白的不良底物（外排率> 1）。没有4′-N-取代的化合物的转运（即，环丙沙星和CNV 97100）有利于分泌（流出率> 4）。CNV 97100转运的进一步表征显示其是浓度依赖性的（表观Km = 0.484 mM，表观Vmax = 17.5 nmol · cm−2· h−1），温度依赖性（Ea= 20.57（PAB）和31.45 kcal/mol（PBA））。p-糖蛋白（p-gp）抑制剂，如维拉帕米（100 μM）和环孢菌素A CsA（20 μM）显著抑制PBA（p< 0.05），但显著增强PAB（p< 0.05）。多药耐药相关蛋白（MRP）抑制剂白三烯C4仅降低环丙沙星的PBA（p< 0.05），而对CNV 97100无影响。当维拉帕米浓度增加时，CNV 97100的PBA显著降低（p< 0.05），IC_（90）值为96.5 μM。综上所述，这些结果表明氟喹诺酮类药物的4′-N-烷基化改善了其吸收渗透性。CNV 97100的分泌主要是通过-gp，而环丙沙星的分泌是通过外排转运蛋白的组合。© 2002 Wiley-Liss公司。和美国制药协会
The kinetics of transport of a new fluoroquinolone antibiotic (CNV97100) and its analogs were characterized using the Caco-2 cell culture model. Unidirectional permeabilities of these analogs were greater (p< 0.05) than that of ciprofloxacin. The absorptive permeabilities (PAB) of 4′-N-substituted analogs (CNV97101-104) were 400–600% greater, whereas the secretory permeability (PBA) was 25–80% greater than unsubstituted analogs because CNV97101-104 were poor substrates for efflux transporters (efflux ratio ≈ 1). The transport of compounds without 4′-N-substitution (i.e., ciprofloxacin and CNV97100) favored secretion (efflux ratio ≈ 4). Further characterization of CNV97100 transport revealed that it was concentration dependent (apparentKm= 0.484 mM, and apparentVmax= 17.5 nmol · cm−2· h−1), and temperature dependent (Ea= 20.57 forPABand 31.45 kcal/mol forPBA, respectively).p-Glycoprotein (p-gp)inhibitors, such as verapamil (100 μM) and cyclosporin A (CsA, 20 μM) significantly (p< 0.05) inhibitedPBAbut significantly (p< 0.05) enhancedPAB. Multidrug resistance related protein (MRP) inhibitor leukotriene C4only decreased (p< 0.05)PBAof ciprofloxacin but not that of CNV97100. In the presence of increasing concentrations of verapamil, thePBAof CNV97100 decreased significantly (p< 0.05), with an IC90value of 96.5 μM. Taken together, these results suggested that 4′-N-alkylation of fluoroquinolones improves their absorptive permeability. Secretion of CNV97100 is dominated byp-gp, whereas the secretion of ciprofloxacin is via a combination of efflux transporters. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association