Adenosine triphosphate binding cassette transporters such as P-glycoprotein (PGP) play an important role in drug pharmacokinetics by actively effluxing their substrates at barrier interfaces, including the blood-brain, blood-cerebrospinal fluid (CSF) and placental barriers. For a molecule to access the brain during fetal stages it must bypass efflux transporters at both the placental barrier and brain barriers themselves. Following birth, placental protection is no longer present and brain barriers remain the major line of defense. Understanding developmental differences that exist in the transfer of PGP substrates into the brain is important for ensuring that medication regimes are safe and appropriate for all patients. In the present study PGP substrate rhodamine-123 (R123) was injected intraperitoneally into E19 dams, postnatal (P4, P14) and adult rats. Naturally fluorescent properties of R123 were utilized to measure its concentration in blood-plasma, CSF and brain by spectrofluorimetry (Clariostar). Statistical differences in R123 transfer (concentration ratios between tissue and plasma ratios) were determined using Kruskal-Wallis tests with Dunn’s corrections. Following maternal injection the transfer of R123 across the E19 placenta from maternal blood to fetal blood was around 20 %. Of the R123 that reached fetal circulation 43 % transferred into brain and 38 % into CSF. The transfer of R123 from blood to brain and CSF was lower in postnatal pups and decreased with age (brain: 43 % at P4, 22 % at P14 and 9 % in adults; CSF: 8 % at P4, 8 % at P14 and 1 % in adults). Transfer from maternal blood across placental and brain barriers into fetal brain was approximately 9 %, similar to the transfer across adult blood-brain barriers (also 9 %). Following birth when placental protection was no longer present, transfer of R123 from blood into the newborn brain was significantly higher than into adult brain (3 fold, p < 0.05). Administration of a PGP substrate to infant rats resulted in a higher transfer into the brain than equivalent doses at later stages of life or equivalent maternal doses during gestation. Toxicological testing of PGP substrate drugs should consider the possibility of these patient specific differences in safety analysis.

中文翻译：

---

罗丹明 123 转移到胎儿、新生和成年大鼠的大脑和脑脊液中

三磷酸腺苷结合盒转运蛋白，如 P-糖蛋白 (PGP)，通过在屏障界面主动流出其底物，包括血脑、血脑脊液 (CSF) 和胎盘屏障，在药物药代动力学中发挥重要作用。对于在胎儿阶段进入大脑的分子，它必须绕过胎盘屏障和大脑屏障本身的外排转运蛋白。出生后，胎盘保护不再存在，脑屏障仍然是主要的防线。了解 PGP 底物转移到大脑中存在的发育差异对于确保药物治疗对所有患者都是安全和合适的很重要。在本研究中，产后（P4 P14) 和成年大鼠。R123 的自然荧光特性用于通过荧光分光光度法 (Clariostar) 测量其在血浆、CSF 和大脑中的浓度。R123 转移（组织和血浆比率之间的浓度比）的统计差异使用带有 Dunn 校正的 Kruskal-Wallis 检验确定。母体注射后，R123 通过 E19 胎盘从母体血液转移到胎儿血液的比例约为 20%。在到达胎儿循环的 R123 中，43% 转移到大脑中，38% 转移到脑脊液中。R123 从血液到大脑和 CSF 的转移在出生后幼崽中较低，并随着年龄的增长而减少（大脑：P4 时为 43%，P14 时为 22%，成人为 9%；CSF：P4 时为 8%，P14 和 1 时为 8% % 成人）。从母血通过胎盘和脑屏障进入胎儿脑的转移率约为 9%，类似于跨越成人血脑屏障的转移（也是 9%）。出生后，当胎盘保护不再存在时，R123 从血液转移到新生儿大脑的比例显着高于成人大脑（3 倍，p < 0.05）。与生命后期的等效剂量或妊娠期间的等效母体剂量相比，向幼鼠施用 PGP 底物导致更高的转移到大脑中。PGP 底物药物的毒理学测试应在安全性分析中考虑这些患者特异性差异的可能性。与生命后期的等效剂量或妊娠期间的等效母体剂量相比，向幼鼠施用 PGP 底物导致更高的转移到大脑中。PGP 底物药物的毒理学测试应在安全性分析中考虑这些患者特异性差异的可能性。与生命后期的等效剂量或妊娠期间的等效母体剂量相比，向幼鼠施用 PGP 底物导致更高的转移到大脑中。PGP 底物药物的毒理学测试应在安全性分析中考虑这些患者特异性差异的可能性。