中文摘要：

研究治疗胎儿快速性心律失常的一系列药物在过表达乳腺癌耐药蛋白（breast cancer resistance protein,BCRP）的马丁达比犬肾上皮细胞系MDCKII-BCRP单层细胞模型中的跨膜转运机制,筛选BCRP底物。利用MDCKII-BCRP和MDCKII单层细胞模型研究索他洛尔（sotalol）、普萘洛尔（propranolol）、普罗帕酮（propafenone）、普鲁卡因胺（procainamide）及氟卡尼（flecainide）的双向转运特性,采用HPLC或化学发光仪测定药物含量,计算其表观渗透系数（Papp）、外排率（RE）和净外排率（Rnet）,将Rnet〉1.5的药物进行细胞蓄积实验,考察药物浓度和BCRP抑制剂槲皮素对该药细胞内蓄积的影响。所选择的药物中,索他洛尔、普萘洛尔、普罗帕酮和普鲁卡因胺在两种细胞单层顶侧（apical,A）→基底侧（basolateral,B）的转运与B→A的转运之间无显著性差异,Rnet均小于1.5;氟卡尼浓度为20和5μmol·L-1时,Rnet分别为1.6和1.9。细胞蓄积实验证实氟卡尼在MDCKII、MDCKIIBCRP细胞内蓄积具有浓度依赖性,且MDCKII-BCRP细胞内的蓄积量明显低于MDCKII细胞;当同时在MDCKII-BCRP细胞内加入50μmol·L-1槲皮素时,氟卡尼在细胞中的蓄积量显著增加（P〈0.05）。结果初步提示,索他洛尔、普萘洛尔、普罗帕酮和普鲁卡因胺可能不是BCRP底物;而氟卡尼可能是BCRP底物,因此母体用该药治疗胎儿快速性心律失常时,母体胎盘滋养层细胞膜上表达的BCRP极有可能会介导其外排,从而显著影响治疗效果。

英文摘要：

To study the transport mechanisms of drugs for transplacental treatment of fetal tachyarrhythmia, MDCKII-BCRP and MDCKII cell models was used. MDCKII-BCRP and MDCKII cell monolayer model was used to investigate the bi-direction transport of sotalol, propranolol, propafenone, procainamide and flecainide. Drug concentrations were measured by HPLC-UV or chemiluminescence. The apparent permeability coefficient （Papp）, efflux rate （RE） and net efflux rate （R_net） were calculated. Drugs with Rnet greater than 1.5 were further investigated using cellular accumulation experiments with or without a BCRP inhibitor. The Rnet of sotalol, propranolol, propafenone and procainamide were less than 1.5, while Rnet of flecainide with concentrations of 20 and 5 μmol·L^-1 were 1.6 and 1.9, respectively. The results showed that the transport offlecainide on MDCKII- BCRP cell monolayer could be mediated by BCRP; and the affinity increased when the concentration of flecainide decreased. Cellular accumulation experiments further suggested that accumulation of flecainide in MDCKII-BCRP cells was significantly lower than that in MDCKII ceils in a concentration-dependent manner. BCRP inhibitor quercetin （50 μmo·L^-1） significantly increased the accumulation of flecainide in MDCKII- BCRP cells （P〈0.05）. Our preliminary data showed that flecainide but not sotalol, propranolol, propafenone or procainamide can be a substrate of BCRP. Thus the effect of flecainide may be affected by the BCRP in the maternal placental trophoblast membrane layer when treating fetal tachyarrhythmia.