Cox E H, Langemeijer M W, Gubbens-Stibbe J M, Muir K T, Danhof M
Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.
Anesthesiology. 1999 Feb;90(2):535-44. doi: 10.1097/00000542-199902000-00030.
The purpose of this study was to investigate the in vivo pharmacodynamics and the pharmacodynamic interactions of remifentanil and its major metabolite, GR90291, in a rat electroencephalographic model.
Remifentanil and GR90291 were administered according to a stepwise infusion scheme. The time course of the electroencephalographic effect (0.5-4.5 Hz) was determined in conjunction with concentrations of the parent drug and the metabolite in blood.
Administration of remifentanil resulted in concentrations of remifentanil and GR90291 in the ranges 0-120 ng/ml and 0-850 ng/ml, respectively. When the metabolite was administered, concentrations of the metabolite in the range 0-220 microg/ml and no measurable concentrations of remifentanil were observed. The mean +/- SE values of the pharmacokinetic parameters clearance and volume of distribution at steady state were 920+/-110 ml x min(-1) x kg(-1) and 1.00+/-0.93 l/kg for remifentanil and 15+/-2 ml x min(-1) x kg(-1) and 0.56+/-0.08 l/kg for GR90291. The relative free concentrations in the brain, as determined on the basis of the cerebrospinal fluid/total blood concentration ratio at steady state, were 25+/-5% and 0.30+/-0.11% for remifentanil and GR90291, respectively. Concentration-electroencephalographic effect relations were characterized on the basis of the sigmoidal Emax pharmacodynamic model. The mean +/- SE values for the maximal effect (Emax), the concentration at which 50% of the maximal effect is obtained (EC50), and Hill factor for remifentanil were 109+/-12 microV, 9.4+/-0.9 ng/ml, and 2.2+/-0.3, respectively (n = 8). For GR90291, the mean +/- SE values for EC50 and the Hill factor were 103,000+/-9,000 microg/ml and 2.5+/-0.4, respectively (n = 6).
Analysis of the data on the basis of a previously postulated, mechanism-based pharmacokinetic-pharmacodynamic model for synthetic opioids revealed that the low in vivo potency of GR90291 can be explained by a low affinity to the mu-opioid receptor in combination with a poor brain penetration.
本研究的目的是在大鼠脑电图模型中研究瑞芬太尼及其主要代谢产物GR90291的体内药效学及药效学相互作用。
按照逐步输注方案给予瑞芬太尼和GR90291。结合母体药物和代谢产物在血液中的浓度，测定脑电图效应（0.5 - 4.5 Hz）的时间进程。
给予瑞芬太尼后，瑞芬太尼和GR90291的浓度分别在0 - 120 ng/ml和0 - 850 ng/ml范围内。给予代谢产物时，观察到代谢产物浓度在0 - 220 μg/ml范围内，未检测到瑞芬太尼浓度。瑞芬太尼稳态时药代动力学参数清除率和分布容积的均值±标准误分别为920±110 ml·min⁻¹·kg⁻¹和1.00±0.93 l/kg，GR90291分别为15±2 ml·min⁻¹·kg⁻¹和0.56±0.08 l/kg。根据稳态时脑脊液/全血浓度比确定的脑中相对游离浓度，瑞芬太尼和GR90291分别为25±5%和0.30±0.11%。基于S形Emax药效学模型对浓度 - 脑电图效应关系进行了表征。瑞芬太尼的最大效应（Emax）、产生50%最大效应时的浓度（EC50）和Hill系数的均值±标准误分别为109±12 μV、9.4±0.9 ng/ml和2.2±0.3（n = 8）。对于GR90291，EC50和Hill系数的均值±标准误分别为103,000±9,000 μg/ml和2.5±0.4（n = 6）。
基于先前假定的、基于机制的合成阿片类药物药代动力学 - 药效学模型对数据进行分析表明，GR90291体内效价低可归因于其对μ - 阿片受体亲和力低以及脑内渗透性差。
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