Greene Raymond F, Miser Angela W, Lester Cindy M, Balis Frank M, Poplack David G
Department of Pharmacology, George Washington University Medical Center, Washington, DC, USA Clinical Pharmacology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 U.S.A. Pediatrie Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 U.S.A.
Pain. 1987 Sep;30(3):339-348. doi: 10.1016/0304-3959(87)90022-4.
The cerebrospinal fluid (CSF) and plasma pharmacokinetics of morphine administered as a continuous infusion were studied in pediatric cancer patients and in monkeys with implanted Ommaya reservoirs. In monkeys administered a constant infusion of 0.15 mg morphine sulfate/kg/h, morphine steady-state plasma and CSF concentrations were 84.4 +/- 20.0 ng/ml and 25.3 +/- 4.9 ng/ml, respectively, for a CSF:plasma ratio of 0.30 +/- 0.05. For comparison, the monkeys also received morphine as an intravenous bolus at a dose of 0.45 mg morphine sulfate/kg. The CSF:plasma area under the concentration-time curve (AUC) ratio was 0.40 +/- 0.07, similar to that seen with continuous infusion. Morphine pharmacokinetics were also studied in cancer patients administered long-term infusions of morphine sulfate over a wide dosage range (0.04-31 mg/kg/h). The steady-state plasma concentration of morphine was linearly related to the infusion rate although variability was noted. The average clearance value was 23 ml/min/kg which is at the upper end of the estimates reported for morphine clearance using bolus administration. No evidence for morphine accumulation using long-term administration was observed. A limited number of CSF samples obtained by lumbar puncture showed comparable CSF and plasma concentrations of unbound morphine assuming morphine is approximately 30% bound in human plasma.
在患有儿科癌症的患者以及植入了奥马亚储液器的猴子身上，研究了持续输注吗啡后的脑脊液（CSF）和血浆药代动力学。在以0.15毫克硫酸吗啡/千克/小时的恒定速率输注的猴子中，吗啡的稳态血浆浓度和脑脊液浓度分别为84.4±20.0纳克/毫升和25.3±4.9纳克/毫升，脑脊液与血浆的比率为0.30±0.05。作为对比，这些猴子还接受了剂量为0.45毫克硫酸吗啡/千克的静脉推注吗啡。浓度-时间曲线下面积（AUC）的脑脊液与血浆比率为0.40±0.07，与持续输注时观察到的比率相似。还在接受硫酸吗啡长期输注、剂量范围较宽（0.04 - 31毫克/千克/小时）的癌症患者中研究了吗啡的药代动力学。尽管存在变异性，但吗啡的稳态血浆浓度与输注速率呈线性相关。平均清除率值为23毫升/分钟/千克，这处于使用推注给药法所报道的吗啡清除率估计值的上限。未观察到长期给药时吗啡蓄积的证据。通过腰椎穿刺获得的少量脑脊液样本显示，假设吗啡在人血浆中的结合率约为30%，未结合吗啡的脑脊液和血浆浓度相当。
