单次推注丙泊酚对日本猕猴（食蟹猕猴指名亚种）的催眠作用及药代动力学[已校正]

Hypnotic effects and pharmacokinetics of a single bolus dose of propofol in Japanese macaques (Macaca fuscata fuscata). [corrected].

作者信息

Miyabe-Nishiwaki Takako, Masui Kenichi, Kaneko Akihisa, Nishiwaki Koki, Shimbo Etsuko, Kanazawa Hideko

机构信息

Centre of Human Evolution Modelling Research, Primate Research Institute, Kyoto University, Inuyama, Aichi, Japan.

出版信息

Vet Anaesth Analg. 2010 Nov;37(6):501-10. doi: 10.1111/j.1467-2995.2010.00564.x.

DOI:10.1111/j.1467-2995.2010.00564.x

PMID:21040374

Abstract

OBJECTIVE

To describe the hypnotic effects of a single bolus dose of propofol in Japanese macaques, and to develop a pharmacokinetic model.

STUDY DESIGN

Prospective experimental trial.

ANIMALS

Four male macaques (5-6 years old, 8.0-11.2 kg).

METHODS

The macaque was restrained and 8 mg kg(-1) of propofol was administrated intravenously at 6 mg kg(-1) minute(-1) . Behavioural changes without stimuli (first experiment) then responses to external stimuli (the second experiment) were assessed every 2 minutes for 20 minutes. Venous blood samples were collected before and at 1, 5, 15, 30, 60, 120 and 210 minutes after drug administration, and plasma concentrations of propofol were measured (third experiment). Pharmacokinetic modelling was performed using NONMEM VI.

RESULTS

Macaques were recumbent without voluntary movement for a mean 14.0 ± 2.7 SD (range 10.5-16.2) or 10.0 ± 3.4 (7.2-14.5)minutes and recovered to behave as pre-administration by 25.1 ± 3.6 (22.1-30.1) or 22.2 ± 1.5 (21.1-24.3) minutes after the end of propofol administration without or with stimuli, respectively. Respiratory and heart rates were stable throughout the experiments (28-68 breaths minute(-1) and 72-144 beats minute(-1) , respectively). Our final pharmacokinetic model included three compartments and well described the plasma concentration of propofol. The population pharmacokinetic parameters were: V(1)=10.4 L, V(2)=8.38 L, V(3)=72.7 L, CL(1)=0.442 L minute(-1), CL(2)=1.14 L minute(-1), CL(3)= 0.313 L minute(-1), (the volumes of distribution and the clearances for the central, rapid and slow peripheral compartments, respectively).

CONCLUSIONS

Intravenous administration of propofol (8 mg kg(-1)) at 6 mg kg(-1)minute(-1) to Japanese macaques had a hypnotic effect lasting more than 7 minutes. A three-compartment model described propofol plasma concentrations over more than 3 hours.

CLINICAL RELEVANCE

The developed pharmacokinetic parameters may enable simulations of administration protocols to maintain adequate plasma concentration of propofol.

摘要

目的

描述单次静脉推注丙泊酚对日本猕猴的催眠作用，并建立药代动力学模型。

研究设计

前瞻性实验性试验。

动物

4只雄性猕猴（5 - 6岁，体重8.0 - 11.2千克）。

方法

将猕猴固定，以6毫克/千克·分钟⁻¹的速度静脉注射8毫克/千克的丙泊酚。在无刺激情况下（第一个实验），然后在有外部刺激情况下（第二个实验），每隔2分钟评估行为变化，持续20分钟。在给药前以及给药后1、5、15、30、60、120和210分钟采集静脉血样，测定丙泊酚的血浆浓度（第三个实验）。使用NONMEM VI进行药代动力学建模。

结果

在无刺激或有刺激情况下，丙泊酚给药结束后，猕猴平均有14.0 ± 2.7标准差（范围10.5 - 16.2）或10.0 ± 3.4（7.2 - 14.5）分钟呈卧位且无自主活动，并分别在25.1 ± 3.6（22.1 - 30.1）或22.2 ± 1.5（21.1 - 24.3）分钟恢复到给药前的行为状态。在整个实验过程中呼吸和心率稳定（分别为28 - 68次/分钟和72 - 144次/分钟）。我们最终的药代动力学模型包括三个房室，能很好地描述丙泊酚的血浆浓度。群体药代动力学参数为：V(1)=10.4升，V(2)=8.38升，V(3)=72.7升，CL(1)=0.442升/分钟，CL(2)=1.14升/分钟，CL(3)=0.313升/分钟（分别为中央、快速和缓慢外周房室的分布容积和清除率）。