Kelley S D, Cauldwell C B, Fisher D M, Lau M, Sharma M L, Weisiger R A
Department of Anesthesia, University of California, San Francisco 94143-0648.
Anesthesiology. 1995 Jan;82(1):251-8. doi: 10.1097/00000542-199501000-00030.
To determine whether liver preservation before transplantation impairs hepatic drug metabolism, hepatic extraction of drugs with different metabolic pathways (fentanyl, morphine, and vecuronium) in isolated rat livers was measured either immediately or after 24 h of hypothermia at 4 degrees C using a standard preservation-reperfusion sequence.
Isolated rat livers were perfused via the portal vein for 30 min to document initial viability. Test livers (n = 5) were perfused with iced Belzer solution, stored for 24 h at 4 degrees C, and flushed with 6% hetastarch. After hypothermic preservation for 24 h, or in control livers (n = 5) immediately after the 30-min perfusion, livers were perfused single-pass at a constant flow rate with solutions containing fentanyl, morphine, and vecuronium at 37 degrees C. Perfusate and bile samples were obtained at regular intervals for 64 min, after which liver tissue was harvested for analysis. Drug concentrations were measured using radioimmunoassay and gas chromatography. Metabolic capacity of the liver was estimated from the extraction fraction of each drug at steady-state.
After warming to 37 degrees C, preserved livers consumed oxygen and produced bile at rates similar to that of control livers. Hypothermic preservation did not affect extraction of fentanyl and morphine. Vecuronium extraction was initially less in preserved livers, but this difference disappeared as the preserved livers returned to 37 degrees C (< 16 min). Biliary excretion and tissue concentrations of vecuronium were similar in each group.
Hypothermic preservation does not significantly impair extraction of these drugs in this liver preservation model. If these results apply to human liver transplantation, little danger of drug accumulation exists during the early postoperative period if hepatic function is normal.
为了确定移植前肝脏保存是否会损害肝脏药物代谢，使用标准的保存 - 再灌注程序，在离体大鼠肝脏中，立即或在4℃低温保存24小时后，测量具有不同代谢途径的药物（芬太尼、吗啡和维库溴铵）的肝脏摄取情况。
通过门静脉对离体大鼠肝脏进行30分钟灌注以记录初始活力。将受试肝脏（n = 5）用冰冷的Belzer溶液灌注，在4℃下保存24小时，并用6%羟乙基淀粉冲洗。在低温保存24小时后，或在对照肝脏（n = 5）30分钟灌注后立即，将肝脏在37℃下以恒定流速进行单通道灌注，灌注液中含有芬太尼、吗啡和维库溴铵。每隔一定时间采集64分钟的灌注液和胆汁样本，之后收获肝脏组织进行分析。使用放射免疫测定法和气相色谱法测量药物浓度。根据每种药物在稳态时的提取分数估计肝脏的代谢能力。
复温至37℃后，保存的肝脏耗氧和产生胆汁的速率与对照肝脏相似。低温保存不影响芬太尼和吗啡的摄取。维库溴铵的摄取在保存的肝脏中最初较低，但随着保存的肝脏恢复到37℃（<16分钟），这种差异消失。每组中维库溴铵的胆汁排泄和组织浓度相似。
在该肝脏保存模型中，低温保存不会显著损害这些药物的摄取。如果这些结果适用于人类肝移植，那么在术后早期，如果肝功能正常，药物蓄积的风险很小。
