Schywalsky M, Ihmsen H, Tzabazis A, Fechner J, Burak E, Vornov J, Schwilden H
University of Erlangen-Nuremberg, Department of Anaesthesiology, Erlangen, Germany.
Eur J Anaesthesiol. 2003 Mar;20(3):182-90. doi: 10.1017/s0265021503000322.
We studied the pharmacokinetics and pharmacodynamics of GPI 15715 (Aquavan injection), a new water-soluble prodrug metabolized to propofol by hydrolysis.
Nine adult male Sprague-Dawley rats (398 +/- 31 g) received a bolus dose of 40 mg GPI 15715. The plasma concentrations of GPI 15715 and propofol were determined from arterial blood samples, and the pharmacokinetics of both compounds were investigated using compartment models whereby the elimination from the central compartment of GPI 15715 was used as drug input for the central compartment of propofol. Pharmacodynamics were assessed using the median frequency of the EEG power spectrum.
A maximum propofol concentration of 7.1 +/- 1.7 microg mL(-1) was reached 3.7 +/- 0.2 min after bolus administration. Pharmacokinetics were best described by two-compartment models. GPI 15715 showed a short half-life (2.9 +/- 0.2 and 23.9 +/- 9.9 min), an elimination rate constant of 0.18 +/- 0.01 min(-1) and a central volume of distribution of 0.25 +/- 0.02 L kg(-1). For propofol, the half-life was 1.9 +/- 0.1 and 45 +/- 7 min, the elimination rate constant was 0.15 +/- 0.02 min(-1) and the central volume of distribution was 2.3 +/- 0.6 L kg(-1). The maximum effect on the electroencephalogram (EEG)--EEG suppression for >4 s--occurred 6.5 +/- 1.2 min after bolus administration and baseline values of the EEG median frequency were regained 30 min later. The EEG effect could be described by a sigmoid Emax model including an effect compartment (E0 = 16.9 +/- 7.9 Hz, EC50 = 2.6 +/- 0.8 microg mL(-1), ke0 = 0.35 +/- 0.04 min(-1)).
Compared with known propofol formulations, propofol from GPI 15715 showed a longer half-life, an increased volume of distribution, a delayed onset, a sustained duration of action and a greater potency with respect to concentration.
我们研究了GPI 15715（阿夸凡注射液）的药代动力学和药效学，GPI 15715是一种新的水溶性前体药物，通过水解代谢为丙泊酚。
9只成年雄性Sprague-Dawley大鼠（体重398±31 g）接受40 mg GPI 15715的单次静脉推注剂量。从动脉血样中测定GPI 15715和丙泊酚的血浆浓度，并使用房室模型研究两种化合物的药代动力学，其中将GPI 15715从中央房室的消除作为丙泊酚中央房室的药物输入。使用脑电图功率谱的中位频率评估药效学。
静脉推注后3.7±0.2分钟达到丙泊酚的最大浓度，为7.1±1.7 μg mL⁻¹。药代动力学用二房室模型描述最佳。GPI 15715的半衰期较短（2.9±0.2和23.9±9.9分钟），消除速率常数为0.18±0.01分钟⁻¹，中央分布容积为0.25±0.02 L kg⁻¹。对于丙泊酚，半衰期为1.9±0.1和45±7分钟，消除速率常数为0.15±0.02分钟⁻¹，中央分布容积为2.3±0.6 L kg⁻¹。对脑电图（EEG）的最大效应——EEG抑制>4秒——在静脉推注后6.5±1.2分钟出现，30分钟后EEG中位频率恢复到基线值。EEG效应可用包含效应室的S形Emax模型描述（E0 = 16.9±7.9 Hz，EC50 = 2.6±0.8 μg mL⁻¹，ke0 = 0.35±0.04分钟⁻¹）。
与已知的丙泊酚制剂相比，GPI 15715产生的丙泊酚半衰期更长，分布容积增加，起效延迟，作用持续时间延长，且在浓度方面效力更强。
