人胎盘ATP结合盒转运蛋白对格列本脲胎盘转运的影响

Role of the ATP-binding cassette efflux transporters in the transplacental transfer of glyburide

目的研究成熟胎盘ATP结合盒转运蛋白对格列本脲胎盘透过率的影响。方法建立人胎盘体外循环灌注模型40例,分为4组(n=10),分别用格列本脲、格列本脲和维拉帕米(PGP抑制剂组)、格列本脲和尼卡地平(BCRP抑制剂组)、格列本脲和吲哚美辛(MRPs抑制剂组)循环灌注3 h,计算各组格列本脲的胎盘透过率和清除指数。结果3 h循环结束后,4组格列本脲的平均胎盘透过率分别为(0.78±0.66)%、(2.17±0.90)%、(1.45±0.70)%、(3.65±2.10)%,与格列本脲组相比,加入抑制剂后各组格列本脲胎盘透过率均有增加(P<0.05),MRPs抑制剂组透过率高于PGP抑制剂组和BCRP抑制剂组(P<0.05);4组格列本脲相对透过率分别为(0.03±0.02)、(0.08±0.04)、(0.05±0.02)、(0.13±0.05),PGP抑制剂组和MRPs抑制剂组的清除指数均高于格列本脲组(P<0.05),且MRPs抑制剂组高于PGP抑制剂组(P<0.05)。结论PGP、BCRP、MRPs抑制剂均不同程度地参与了格列本脲的胎盘转运,其中,MRPs抑制剂的影响可能更为显著。

Objective To determine the role of ATP-binding cassette efflux transporters in the transport of glyburide across the human placenta.Methods The ex vivo human placental transfer of glyburide from the maternal circulation to the fetal circulation was conducted on 40 mature placentas from healthy term pregnancies.Perfusion was conducted in 4 groups:glyburide,glyburide and verapamil(PGP inhibitors),glyburide and nicardipine(BCRP inhibitors),and glyburide and indomethacin(MRPs inhibitors)group.Each perfusion lasted 3 hours.Results After 3 hours of perfusion,the fetal transfer rates of glyburide were(0.78±0.66)%for glyburide,(2.17±0.90)%for PGP inhibitor,(1.45±0.70)%for BCRP inhibitors,and(3.65±2.10)%for MRPs inhibitors,respectively.The fetal transfer rates of glyburide were all increased in the presence of 3 specific inhibitors when compared to the mean ratio in the absence of the inhibitors(P<0.05),and MRPs inhibitor showed better effect than the other two inhibitors(P<0.05).In each group,the clearance index of glyburide was(0.03±0.02)for glyburide,(0.08±0.04)for PGP inhibitors,(0.05±0.02)for BCRP inhibitors,and(0.13±0.05)for MRPs inhibitors,respectively.Compared with the glyburide group,PGP inhibitors and MRPs inhibitors group had higher clearance indexes(P<0.05).The clearance index of MRPs inhibitors group was significantly higher than that of PGP inhibitors group(P<0.05).Conclusion PGP,BCRP and MRPs all play a role in the transplacental transfer of glyburide.MRPs may have greater influence.