Department of Clinical Pharmacology, Royal North Shore Hospital, St Leonards, Australia.
J Pharm Sci. 2011 Jan;100(1):334-40. doi: 10.1002/jps.22235. Epub 2010 Jun 16.
The role of the fenestrated liver sinusoidal endothelial cells (LSECs) in the hepatic disposition of paracetamol was investigated in isolated perfused livers from rats treated with poloxamer 407 (P407), a surfactant that causes extensive defenestration of the LSECs. Bolus doses containing tracer amounts of (14)C-paracetamol and reference markers (Evans Blue, (3)H-sucrose) were injected into control rats and rats that had been administered P407 via intra-peritoneal injection 24 h prior to experimentation. Scanning electron microscopy confirmed a reduced number of fenestrations in rats treated with P407. The recovery of paracetamol was significantly increased in P407 rats compared to controls (0.72 ± 0.07 P407 vs. 0.67 ± 0.04 control, p < 0.05) and the volume of distribution of paracetamol as a fraction of the sucrose volume was significantly reduced. The permeability-surface area (PS) product for the transfer of paracetamol across the LSECs was also reduced in the P407 rats (0.032 ± 0.009 P407 vs. 0.043 ± 0.007 mL/s/g controls, p < 0.05). P407 treatment resulted in increased recovery and decreased PS product of paracetamol following a single pass through the isolated perfused liver. This is consistent with exclusion of paracetamol from the space of Disse due to defenestration of the LSECs.
在使用泊洛沙姆 407（P407）处理的大鼠离体灌注肝脏中研究了窗孔状肝窦内皮细胞（LSEC）在扑热息痛的肝脏处置中的作用，P407 是一种导致 LSEC 广泛去窗孔化的表面活性剂。将含有示踪量（14）C-扑热息痛和参考标记物（伊文思蓝、（3）H-蔗糖）的示踪剂剂量的单次推注注射到对照大鼠和在实验前 24 小时通过腹腔内注射给予 P407 的大鼠中。扫描电子显微镜证实，用 P407 处理的大鼠的窗孔数量减少。与对照组相比，P407 大鼠中扑热息痛的回收明显增加（P407 为 0.72±0.07，对照组为 0.67±0.04，p<0.05），并且扑热息痛作为蔗糖体积分数的分布体积明显减少。P407 大鼠中扑热息痛穿过 LSEC 的传递的渗透表面积（PS）产物也减少（P407 为 0.032±0.009，对照组为 0.043±0.007，p<0.05）。P407 处理导致单次通过离体灌注肝脏后扑热息痛的回收率增加和 PS 产物减少。这与 LSEC 的去窗孔化导致扑热息痛从 Disse 腔隙中排除一致。
