Changes in pharmacokinetics of single dose of fentanyl in simulated high altitude in rats

Yukun REN; Zhuo WANG; Xudong XIAO; Zonghong LONG; Yu LI; Qiuyue WANG; Hong LI; Jiaxing LIAO; Rong ZHANG

doi:10.16016/j.2097-0927.202310018

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Changes in pharmacokinetics of single dose of fentanyl in simulated high altitude in rats

Pharmacy | 更新时间：2026-01-09

- Changes in pharmacokinetics of single dose of fentanyl in simulated high altitude in rats
- Journal of Army Medical University Vol. 46, Issue 7, Pages: 732-737(2024)
- 作者机构：
  
  1.400037 重庆, 陆军军医大学(第三军医大学)第二附属医院药剂科
  2.400037 重庆, 陆军军医大学(第三军医大学)第二附属医院麻醉科
  3.250031 济南, 联勤保障部队第九六〇医院麻醉科
- 作者简介：
- 基金信息：
  
  the Clinical Medical Talent Training Program of Army Medical University(2018XLC3032)
- DOI：10.16016/j.2097-0927.202310018
  CLC： R339.54;R969.1;R971.2
- Received：07 October 2023，
  
  Revised：2024-01-12，
  
  Published：15 April 2024
- 稿件说明：
移动端阅览
Yukun REN, Zhuo WANG, Xudong XIAO, et al. Changes in pharmacokinetics of single dose of fentanyl in simulated high altitude in rats[J]. Journal of Army Medical University, 2024, 46(7): 732-737.
DOI：

Yukun REN, Zhuo WANG, Xudong XIAO, et al. Changes in pharmacokinetics of single dose of fentanyl in simulated high altitude in rats[J]. Journal of Army Medical University, 2024, 46(7): 732-737. DOI： 10.16016/j.2097-0927.202310018.

摘要

目的

探索模拟高原环境中大鼠芬太尼单次给药后药代动力学变化及其可能的影响因素。

方法

使用随机数字表法将36只体质量为(250±20) g的健康雌性SD大鼠(6~8周龄)分为模拟高原环境急性暴露组(A组)、慢性暴露组(S组)和对照组(C组)

每组12只。急性暴露组和慢性暴露组在低压舱中模拟5 000 m海拔高度分别饲养3 d和30 d

对照组在舱外(海拔300 m)饲养。每组随机选取6只大鼠

通过股静脉单次给予芬太尼

在给药前及给药后1、2、4、8、15、30、60、120、180 min经股动脉采集血液

采用液相色谱串联质谱法(liquid chromatography tandem mass spectrometry

LC-MS/MS)检测芬太尼血药浓度

使用WinNonlin 8.2软件计算药代动力学特征参数; 剩余6只大鼠通过超声检测门静脉的内径、峰值流速及血流量

并取肝组织进行CYP3A1蛋白含量检测。

结果

急性暴露组和慢性暴露组大鼠在60、120、180 min 3个时间点的血药浓度显著低于对照组(

=0.002

0.001

=0.001)。与对照组比较

急性暴露组清除率(clearance rate

)增加54.06%(

=0.021)

平均驻留时间(MRT

last

)缩短24.21%(

=0.033);慢性暴露组

增加50.10%(

=0.041)

血药浓度-时间曲线下面积(AUC

0-t

、AUC

0-∞

)、MRT

last

分别降低18.92%(

=0.039)、27.54%(

=0.018)、33.61%(

=0.004)。慢性暴露组门静脉内径和血流量较对照组分别增加10.87%(

=0.006)、42.50%(

=0.006)。急性暴露组CYP3A1蛋白含量较对照组升高28.74%(

=0.048)。

结论

模拟高原环境中大鼠芬太尼单次给药后清除速率较平原环境显著加快

该现象可能与模拟高原环境中大鼠肝脏血流量增加以及肝脏CYP3A1蛋白表达增加有关。

Abstract

Objective

To explore the pharmacokinetic changes of single dose of fentanyl in rats in a simulated high-altitude and contributing factors.

Methods

Thirty-six healthy female SD rats (6~8 weeks old

250±20 g) were randomly divided into high-altitude-acute-exposure group (group A)

high-altitude-chronic-exposure group (group S) and control group (group C) through random number table

with 12 rats in each group.The group A and S were housed in a low-pressure chamber simulating the high altitude of 5 000 m above sea level for 3 and 30 d respectively

and the group C was housed out of the chamber (at an altitude of 300 m).A single dose of fentanyl was administered through the femoral vein to 6 rats randomly selected from each group.Liquid chromatography tandem mass spectrometry (LC-MS/MS) was used to detect blood concentrations of fentanyl and WinNonlin 8.2 software was used to calculate the pharmacokinetic parameters

while blood samples were taken through the femoral artery before and in 1

120 and 180 min after administration.The remaining 6 rats were ultrasonographically assessed for portal vein internal diameter (PVD)

peak flow velocity (PVV) and blood flow (PVF)

and liver tissues were collected for CYP3A1 protein content assay.

Results

The blood drug concentrations of fentanyl in the group A and group S were significantly lower than those in the group C at 60

120

and 180 min (

=0.002

0.001

=0.001).Compared with the group C

the clearance rate (

) of the group A was increased by 54.06%(

=0.021)

and the mean residence time (MRT

last

) was shortened by 24.21%(

=0.033);

of the group S was increased by 50.10%(

=0.041)

the area under the concentration-time curve (AUC

0-t

AUC

0-∞

) and MRT

last

were reduced by 18.92%(

=0.039)

27.54%(

=0.018) and 33.61%(

=0.004)

respectively.PVD and PVF in the group S increased by 10.87%(

=0.006) and 42.50%(

=0.006) when compared with the group C.The CYP3A1 protein content in the group A was 28.74%

which was higher than that in the group C (

=0.048).

Conclusion

Fentanyl is cleared significantly faster after a single dose in rats in simulated high-altitude

which may be related to the increased liver blood flow and increased CYP3A1 protein expression in liver.

关键词

Keywords

references

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