D'Honneur G, Gilton A, Sandouk P, Scherrmann J M, Duvaldestin P
Department of Anesthesia, University of Paris, Henri Mondor Hospital, France.
Anesthesiology. 1994 Jul;81(1):87-93. doi: 10.1097/00000542-199407000-00013.
In patients with renal failure, morphine may cause prolonged narcosis and respiratory depression. Accumulation of the pharmacologically active metabolite morphine-6-glucuronide (M-6G) may explain this effect of morphine in patients with renal failure. After a single oral dose, morphine and its conjugates were measured in the plasma and the cerebrospinal fluid (CSF) in patients with renal failure.
Eight patients with normal renal function and six patients with renal failure requiring dialysis were studied after operation under spinal anesthesia. Plasma and CSF concentrations of morphine, morphine-3-glucuronide (M-3G), and M-6G were measured by high-pressure liquid chromatography every 4 h for 24 h after an oral dose of 30 mg morphine.
The area under morphine plasma concentration-time curve from 0 to 24 h increased from 38 +/- 4 ng.ml-1 x h in patients with normal renal function to 110 ng.ml-1 x h in those with renal failure (P < 0.01). In patients with renal failure, plasma concentrations of M-3G and M-6G were higher at 4 h and remained at an increased level until the end of the study. The peak CSF concentration of morphine at 8 h was similar in those with renal failure or normal renal function, 1.8 +/- 0.4 and 2.0 +/- 0.6 ng.ml-1 respectively. M-3G and M-6G in CSF reached a maximum at 12 h in patients with normal renal function, whereas in those with renal failure the concentrations gradually increased so that the highest concentrations were observed at 24 h. At 24 h, CSF M-6G concentration was 15 times greater in patients with renal failure than in those with normal renal function.
We conclude that M-3G and M-6G readily cross the blood-brain barrier in patients with normal renal function or with renal failure. In patients with renal failure, the retention of plasma M-6G induces a progressive accumulation of this active metabolite in CSF; this accumulation may explain the increased susceptibility to morphine in patients with renal failure.
在肾衰竭患者中，吗啡可能导致麻醉时间延长和呼吸抑制。具有药理活性的代谢产物吗啡-6-葡萄糖醛酸（M-6G）的蓄积可能解释了吗啡在肾衰竭患者中的这种作用。单次口服给药后，对肾衰竭患者的血浆和脑脊液（CSF）中的吗啡及其结合物进行了测定。
对8例肾功能正常患者和6例需要透析的肾衰竭患者在脊髓麻醉下手术后进行研究。口服30mg吗啡后，每4小时通过高压液相色谱法测定血浆和脑脊液中吗啡、吗啡-3-葡萄糖醛酸（M-3G）和M-6G的浓度，共持续24小时。
0至24小时吗啡血浆浓度-时间曲线下面积从肾功能正常患者的38±4ng·ml-1·h增加到肾衰竭患者的110ng·ml-1·h（P<0.01）。在肾衰竭患者中，M-3G和M-6G的血浆浓度在4小时时较高，并在研究结束前一直维持在升高水平。肾衰竭患者和肾功能正常患者在8小时时脑脊液中吗啡的峰值浓度相似，分别为1.8±0.4和2.0±0.6ng·ml-1。脑脊液中的M-3G和M-6G在肾功能正常患者中于12小时达到最大值，而在肾衰竭患者中浓度逐渐升高，因此在24小时时观察到最高浓度。在24小时时，肾衰竭患者脑脊液中M-6G的浓度比肾功能正常患者高15倍。
我们得出结论，M-3G和M-6G在肾功能正常或肾衰竭患者中容易穿过血脑屏障。在肾衰竭患者中，血浆M-6G的潴留导致这种活性代谢产物在脑脊液中逐渐蓄积；这种蓄积可能解释了肾衰竭患者对吗啡易感性增加的原因。
