大鼠中的丙泊酚：非线性药代动力学测试及对脑电图效应的急性耐受性建模

Propofol in rats: testing for nonlinear pharmacokinetics and modelling acute tolerance to EEG effects.

作者信息

Ihmsen H, Tzabazis A, Schywalsky M, Schwilden H

机构信息

University of Erlangen-Nuremberg, Department of Anaesthesiology, Erlangen, Germany.

出版信息

Eur J Anaesthesiol. 2002 Mar;19(3):177-88. doi: 10.1017/s0265021502000327.

DOI:10.1017/s0265021502000327

PMID:12071237

Abstract

BACKGROUND AND OBJECTIVE

Pharmacokinetics of propofol in rats have usually been described using linear models. Furthermore, there are only a few investigations for a pharmacodynamic model of the electroencephalographic effects of propofol in rats. We investigated pharmacokinetics and pharmacodynamics of propofol in rats with special regard to linearity in pharmacokinetics and development of tolerance.

METHODS

Twelve adult male Sprague-Dawley rats received propofol in three successive infusion periods of 30 min each with infusion rates of 0.5, 1 and 0.5 mg kg(-1) min(-1). Propofol plasma concentrations were determined from arterial blood samples. Pharmacokinetics were tested for linearity using the ratio of the concentrations at the end of the first and second infusion interval as a model independent criterion. Several linear and nonlinear models were investigated with population pharmacokinetic analysis. Pharmacodynamics were analysed using the median frequency of the electroencephalographic power spectrum as a quantitative measure of the hypnotic effect.

RESULTS

Pharmacokinetics were found to be nonlinear and were best described by a two-compartment model with Michaelis-Menten elimination (Vm = 2.17 microg mL(-1) min(-1), Km = 2.65 microg mL(-1), k12 = 0.30 min(-1), k21 0.063 min(-1), Vc = 0.13 L). Acute tolerance to the electroencephalographic effect of propofol was observed. The hypnotic effect was best described by a sigmoid Emax model (E0 = 17.8 Hz, Emax = 17.7 Hz, EC50 = 4.1 microg mL(-1), gamma = 2.3, ke0 = 0.36 min(-1)) with competitive antagonism of propofol and a hypothetical drug in an additional tolerance compartment.

CONCLUSIONS

For the applied infusion scheme, propofol pharmacokinetics in rats were nonlinear and a development of tolerance to the electroencephalographic effect of propofol was observed during an infusion time of 90 min.

摘要

背景与目的

丙泊酚在大鼠体内的药代动力学通常采用线性模型描述。此外，关于丙泊酚对大鼠脑电图影响的药效学模型的研究较少。我们研究了丙泊酚在大鼠体内的药代动力学和药效学，特别关注药代动力学的线性和耐受性的发展。

方法

12只成年雄性Sprague-Dawley大鼠在三个连续的30分钟输注期内接受丙泊酚，输注速率分别为0.5、1和0.5mg·kg⁻¹·min⁻¹。从动脉血样中测定丙泊酚血浆浓度。使用第一个和第二个输注间隔结束时浓度的比值作为模型独立标准来测试药代动力学的线性。通过群体药代动力学分析研究了几种线性和非线性模型。使用脑电图功率谱的中位数频率作为催眠效果的定量指标来分析药效学。

结果

发现药代动力学是非线性的，最好用具有米氏消除的二室模型描述（Vm = 2.17μg·mL⁻¹·min⁻¹，Km = 2.65μg·mL⁻¹，k12 = 0.30min⁻¹，k21 = 0.063min⁻¹，Vc = 0.13L）。观察到对丙泊酚脑电图效应的急性耐受性。催眠效果最好用S形Emax模型（E0 = 17.8Hz，Emax = 17.7Hz，EC50 = 4.1μg·mL⁻¹，γ = 2.3，ke0 = 0.36min⁻¹）描述，丙泊酚与额外耐受性隔室中的一种假设药物存在竞争性拮抗作用。