口服及静注乙醇后血中乙醇与β-羟丁酸, 乙酰乙酸,乳酸及丙酮酸浓度关系的探讨:一项群体药效动力学的研究

中国临床药理学与治疗学 ›› 2005, Vol. 10 ›› Issue (1): 29-39.

口服及静注乙醇后血中乙醇与β-羟丁酸, 乙酰乙酸,乳酸及丙酮酸浓度关系的探讨:一项群体药效动力学的研究

万捷^1,2, 李建国³, HUI C ko³, Tom LIONETTI², David T GEORGE², Susan E SHOAF²

¹核工业416 医院(原苏医附二院) 神经内科, 成都 610051, 四川;
²Laboratory of Clinical Studies, NIH, MD 20892, USA;
³Department of Pharmacology, Georgetown University, USA

收稿日期:2004-08-09 修回日期:2004-10-10 出版日期:2005-01-26 发布日期:2020-11-19

Relationship between plasma concentration of β-hydroxybutyrate, acetoacetate, lactate and pyruvate and alcohol after oral or intravenous administration of alcohol to normal human subjects: a population pharmacodynamics (PD) analysis

WAN Jie^1,2, LI Jian-guo³, HUI C ko³, Tom LIONETTI², David T GEORGE², Susan E SHOAF²

¹Department of Neurology, Chengdu 416 Hospital, Chengdu 610051, Sichuang, China;
²Laboratory of Clinical Studies, NIH, Bethesda, MD 20892, USA;
³Department of Pharmacology, Georgetown University, Washington D.C.20007, USA

Received:2004-08-09 Revised:2004-10-10 Online:2005-01-26 Published:2020-11-19
Contact: WAN Jie, male, lecturer, visiting fellow, forgarty, engaged in molecular biology of drug metabolism enzyme, clinical neuropharmacology, therapy of epilepsy and toxi cology.Tel:028-80123498 E-mail:jwan2@yahoo.com
Supported by:
NIH Intramural Research Fund

摘要/Abstract

摘要： 目的: 应用群体药理学方法探讨血浆中乙醇浓度对β-羟丁酸, 乙酰乙酸, 乳酸, 丙酮酸, β-羟丁酸乙酰乙酸(H A) 比值及乳酸丙酮酸(L P) 比值变化的效应。方法: 给14 名健康成人口服剂量相当于1.02 g·L^-1总身体水的乙醇。在另一项实验中, 给8名健康成人静脉注射剂量相当于0.83 g·L^-1总身体水的乙醇。在服用乙醇后380 min 采取静脉血测定乙醇, β-羟丁酸, 乙酰乙酸, 乳酸及丙酮酸的血浆浓度。在静注乙醇后340 min 采血测定上述5 种物质的血浆浓度。结果: 在口服乙醇实验中, C0 为66.6±8.1 mg·dL^-1, 显著低于102mg·dL^-1, (t检验, P <0.001) 。清除相斜率β 为0.229±0.05 mg·dL^-1·min^-1 。在静注实验中, C0 为75.6±10.9 mg·dL^-1, 与83 mg·dL^-1比较无显著性差异, β为0.245±0.05mg·dL^-1·min^-1 。在两项实验中, 我们应用群体间接生理反应模型来拟合乙醇浓度对β-羟丁酸, 乙酰乙酸, 乳酸, 丙酮酸,β-羟丁酸乙酰乙酸比值及乳酸丙酮酸比值变化的效应, 并得出各项参数。同时, 我们发现, 当乙醇的清除相结束时, H A 比值尚未达最大值, 说明在乙醇的零级代谢相时肝脏仍在产生NADH。乳酸和乙醇的关系曲线显示乳酸的变化呈现一种逆时钟方向的滞后。结论: 血L P 比值不适合用作实时肝脏氧化状态的指标。本研究提供的参数将有益于将来研究乙醇对肝脏氧化状态的影响。

关键词: 药代动力学, 药效动力学, 群体药效学, 乙醇, β-羟丁酸

Abstract: AIM: To investigate the relationship between plasma concentration of β-hydroxybutyrate, acetoacetate, lactate, pyruvate, β-hydroxybutyrate acetoacetate (H/A ratio) and lactate/pyruvate (L/P ratio) and alcohol by population PD analysis after oral or intravenous administration of alcohol.METHODS: An oral dose of alcohol equivalent to 1.02 g·L^-1total body water was administered to 14 normal human subjects and an IV infusion (30 min) dose of alcohol equivalent to 0.83 g·L^-1total body water was administered to 8 normal subjects.Venous blood was sampled for determination of alcohol (BAC), β-hydroxybutyrate, acetoacetate, lactate and pyruvate for 380 min after oral administration and for 340 min after IV administration.RESULTS: After oral administration, the average of C0 for BAC was 666±81 mg·L^-1, and it was significantly lower than 1 020 mg·L^-1(P <0.001). The slope β for eliminate-phase was 2.29±0.50 mg·L^-1·min^-1.After IV administration, C0 was 756±109 mg·L^-1, and the slope β for eliminate-phase was 2.45±0.51 mg·L^-1·min^-1.The C0 was not significantly different from the expected value of 830 mg·L^-1.After oral or IV administration, the relationship between BAC and β-hydroxybutyrate, acetoacetate, lactate and pyruvate concentration and H/A and L/P ratio were investigated by population physiologic indirect response model, and the parameters were presented.Meanwhile, the H A did not reach maximum at the end of the elimination phase of the alcohol, and it suggested that the liver continue to accumulate NADH at zero-orden metabolism phase of alcohol. The plot of BAC versus the plasma concentration of lactate showed an apparent counter-clockwise hysteresis.CONCLUSION: In general, venous blood L P ratio is not a suitable index for the real time reflection of liver redox status because of the time lag change in concentration of lactate after administration of ethanol.The parameters provided here can be useful for future researches on the effect of alcohol on liver redox status.

Key words: pharmacokinetics, pharmacodynamics, population PD model, ethanol, β-hydroxybutyrate

中图分类号:

R969

万捷, 李建国, HUI C ko, Tom LIONETTI, David T GEORGE, Susan E SHOAF. 口服及静注乙醇后血中乙醇与β-羟丁酸, 乙酰乙酸,乳酸及丙酮酸浓度关系的探讨:一项群体药效动力学的研究[J]. 中国临床药理学与治疗学, 2005, 10(1): 29-39.

WAN Jie, LI Jian-guo, HUI C ko, Tom LIONETTI, David T GEORGE, Susan E SHOAF. Relationship between plasma concentration of β-hydroxybutyrate, acetoacetate, lactate and pyruvate and alcohol after oral or intravenous administration of alcohol to normal human subjects: a population pharmacodynamics (PD) analysis[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2005, 10(1): 29-39.

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