APPLICATION OF PHARMACOKINETICS TO NEUROTRANSMITTER DISPOSITION

药代动力学在神经递质分布中的应用

• 批准号: 4687742
• 负责人: E A LANE
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/4687742
• 关键词: 3 methoxy 4 hydroxyphenylethyleneglycol; antidepressants; cerebrospinal fluid; desipramine; drug metabolism; human subject; liver cirrhosis; liver metabolism; melatonin; neurotransmitter metabolism; norepinephrine

The disposition in human patients of 3-methoxy-4-hydroxy phenylglycol (MHPG), a major metabolite of norepinephrine, has been modeled. The cerebrospinal fluid concentration of MHPG and the urinary excretion rates of its metabolites before and during treatment with desipramine (DMI) and zimelidine (ZIM) were used to evaluate the effect of drug treatment upon the central nervous system rate of production of MHPG. The central rate of production of MHPG was decreased (P less than .05) by 45.7 plus/minus 17.4% by DMI treatment and by 21.4 plus/minus 17.9% by ZIM treatment. A well-stirred model of liver metabolism has been applied to published data on the disposition of melatonin in humans. Melatonin can be described as a substance subject to a large first pass effect of hepatic metabolism. This first pass effect does not appear to account for all of the poor oral bioavailability of melatonin. Although it has been reported that the elimination rate of melatonin is decreased in patients with hepatic cirrhosis, the application of clearance concepts to the same data provides evidence that the endogenous production rate of melatonin is also decreased.

3-甲氧基-4-羟基苯基乙二醇在人类患者中的处置 （MHPG）是去甲肾上腺素的主要代谢物，已被建模。 这 脑脊液中 MHPG 浓度和尿排泄率 地昔帕明 (DMI) 治疗前和治疗期间其代谢物的变化 齐美立定（ZIM）用于评估药物治疗的效果 中枢神经系统产生 MHPG 的速率。 中央利率为 MHPG 产量减少（P 小于 0.05）45.7 ± 17.4% 通过 DMI 治疗，提高 21.4%，通过 ZIM 治疗提高/降低 17.9%。 肝脏代谢的充分搅拌模型已应用于已发表的数据 关于褪黑激素在人体中的分布。 褪黑激素可以描述为 物质受到肝脏代谢的大首过效应。 这 首过效应似乎并不能解释所有不良口腔问题 褪黑激素的生物利用度。 尽管有报道称， 肝病患者褪黑素消除率降低 肝硬化，将清除概念应用于相同的数据提供了 有证据表明褪黑激素的内源性生产率也降低了。