Ishikawa K, Shibanoki S, McGaugh J L
Biochem Pharmacol. 1983 May 1;32(9):1473-8. doi: 10.1016/0006-2952(83)90468-9.
The pharmacokinetics (uptake and elimination) and pharmacodynamics (biochemical effects on monoamine systems) of morphine in the CNS were investigated concurrently. ICR mice, weighing about 25 g, were injected intravenously with several doses (2.5-80 mg/kg) of morphine. The animals were killed by microwave irradiation (5 kW, 0.6 sec) at 10 and 30 min, and 1, 2, 4, 8 and 24 hr after the injection. The intracerebral levels of morphine and metabolically related substances consisting of monoamines [noradrenaline, dopamine (DA), 5-hydroxytryptamine (5-HT), 3, 4-dihydroxyphenylacetic acid (DOPAC), 3-methoxy-4-hydroxyphenylacetic acid [homovanillic acid (HVA)], 5-hydroxyindoleacetic acid (5-HIAA), tyrosine and tryptophan] were determined in identical samples by a combination of organic extraction and high-performance liquid chromatography with electrochemical detection. The intracerebral level of morphine was found to depend on the dose injected, and the biological half-life of the drug was estimated to be about 1 hr. The morphine injection (2.5-80 mg/kg) caused significant increases in monoamine metabolites although only slight changes occurred in the concns of parent transmitters. The intracerebral level of morphine was significantly correlated with the ratios DOPAC/DA and HVA/DA (r = 0.7033, P less than 0.0001; and r = 0.6455, P less than 0.0001, respectively). On the other hand, the correlation between the morphine level and 5-HIAA/5-HT was lower than those for DOPAC/DA and HVA/DA. These results suggest that monoamine systems, especially DA, are closely involved in the biochemical effects of morphine. Furthermore, the proposed procedure is demonstrated to be useful as a new approach in biochemical pharmacology, where the direct correlation between the distribution of a drug (pharmacokinetics) and the biochemical effects of the drug (pharmacodynamics) can be measured.
同时研究了吗啡在中枢神经系统中的药代动力学（摄取和消除）和药效学（对单胺系统的生化作用）。给体重约25克的ICR小鼠静脉注射几种剂量（2.5 - 80毫克/千克）的吗啡。在注射后10分钟、30分钟、1小时、2小时、4小时、8小时和24小时，通过微波辐射（5千瓦，0.6秒）处死动物。通过有机萃取和高效液相色谱结合电化学检测，测定相同样本中吗啡和由单胺组成的代谢相关物质[去甲肾上腺素、多巴胺（DA）、5 - 羟色胺（5 - HT）、3,4 - 二羟基苯乙酸（DOPAC）、3 - 甲氧基 - 4 - 羟基苯乙酸[高香草酸（HVA）]、5 - 羟基吲哚乙酸（5 - HIAA）、酪氨酸和色氨酸]的脑内水平。发现脑内吗啡水平取决于注射剂量，该药物的生物半衰期估计约为1小时。吗啡注射（2.5 - 80毫克/千克）导致单胺代谢产物显著增加，尽管母体递质的浓度仅发生轻微变化。脑内吗啡水平与DOPAC/DA和HVA/DA比值显著相关（r分别为0.7033，P小于0.0001；以及r为0.6455，P小于0.0001）。另一方面，吗啡水平与5 - HIAA/5 - HT之间的相关性低于DOPAC/DA和HVA/DA。这些结果表明单胺系统，尤其是多巴胺，与吗啡的生化作用密切相关。此外，所提出的方法被证明是生化药理学中的一种有用的新方法，其中可以测量药物分布（药代动力学）与药物生化作用（药效学）之间的直接相关性。
