大鼠芬太尼单次给药在模拟高原环境中的药代动力学改变

任玉坤; 王卓; 肖旭东; 龙宗泓; 李钰; 王秋月; 李洪; 廖加兴; 张蓉

doi:10.16016/j.2097-0927.202310018

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大鼠芬太尼单次给药在模拟高原环境中的药代动力学改变

药学 | 更新时间：2026-01-09

- 大鼠芬太尼单次给药在模拟高原环境中的药代动力学改变
- Changes in pharmacokinetics of single dose of fentanyl in simulated high altitude in rats
- 陆军军医大学学报 2024年46卷第7期页码：732-737
- 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：
  
  [张蓉，E-mail：xqpharmacylab@126.comZHANG Rong, E-mail: xqpharmacylab@126.com
- 基金信息：
  
  陆军军医大学临床医学科研人才培养计划(2018XLC3032)
- DOI：10.16016/j.2097-0927.202310018
  中图分类号： R339.54;R969.1;R971.2
- 收稿：2023-10-07，
  
  修回：2024-01-12，
  
  纸质出版：2024-04-15
- 稿件说明：
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任玉坤, 王卓, 肖旭东, 等. 大鼠芬太尼单次给药在模拟高原环境中的药代动力学改变[J]. 陆军军医大学学报, 2024,46(7):732-737.

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.
任玉坤, 王卓, 肖旭东, 等. 大鼠芬太尼单次给药在模拟高原环境中的药代动力学改变[J]. 陆军军医大学学报, 2024,46(7):732-737. DOI： 10.16016/j.2097-0927.202310018.

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

BAILEY D M, STACEY B S, GUMBLETON M. A systematic review and meta-analysis reveals altered drug pharmacokinetics in humans during acute exposure to terrestrial high altitude—clinical justification for dose adjustment?[J]. High Alt Med Biol, 2018, 19(2): 141-148. DOI: 10.1089/ham.2017.0121.

GOLA S, GUPTA A, KESHRI G K, et al . Evaluation of hepatic metabolism and pharmacokinetics of ibuprofen in rats under chronic hypobaric hypoxia for targeted therapy at high altitude[J ] . J Pharm Biomed Anal, 2016, 121: 114-122. DOI: 10.1016/j.jpba.2016.01.018.

ZHU J B, YANG J X, NIAN Y Q, et al . Pharmacokinetics of acetaminophen and metformin hydrochloride in rats after exposure to simulated high altitude hypoxia[J ] . Front Pharmacol, 2021, 12: 692349. DOI: 10.3389/fphar.2021.692349.

周杨. 高原低氧对氯沙坦钾药物代谢动力学的影响[D]. 西宁: 青海大学, 2022.

ZHOU Y. Effect of high altitude hypoxia on pharmacokinetics of losartan potassium[D]. Xining: Qinghai University, 2022

LUO B F, WANG R, LI W B, et al . Pharmacokinetic changes of norfloxacin based on expression of MRP2 after acute exposure to high altitude at 4 300 m[J ] . Biomedecine Pharmacother, 2017, 89: 1078-1085. DOI: 10.1016/j.biopha.2017.02.092.

STANLEY T H. Fentanyl[J]. J Pain Symptom Manag, 2005, 29(5): 67-71. DOI: 10.1016/j.jpainsymman.2005.01.009.

MITRA S, CARLYLE D, KODUMUDI G, et al . New advances in acute postoperative pain management[J ] . Curr Pain Headache Rep, 2018, 22(5): 35. DOI: 10.1007/s11916-018-0690-8.

MILDH L H, SCHEININ H, KIRVELÄ O A. The concentration-effect relationship of the respiratory depressant effects of alfentanil and fentanyl[J]. Anesth Analg, 2001, 93(4): 939-946. DOI: 10.1097/00000539-200110000-00028.

ARNDT J O, MIKAT M, PARASHER C. Fentanyl's analgesic, respiratory, and cardiovascular actions in relation to dose and plasma concentration in unanesthetized dogs[J]. Anesthesiology, 1984, 61(4): 355-361. DOI: 10.1097/00000542-198410000-00001.

NAKAR H, SORKIN A, NADLER R, et al . Trends in prehospital pain management: two decades of point-of-injury care[J ] . Isr Med Assoc J, 2022, 24(9): 584-590.

孙德峰. 加速术后康复理念下术后镇痛管理策略[J]. 实用医学杂志, 2022, 38(17): 2123-2127. DOI: 10.3969/j.issn.1006-5725.2022.17.002.

SUN D F. Postoperative analgesia strategy under concept of ERAS[J]. J Pract Med, 2022, 38(17): 2123-2127. DOI: 10.3969/j.issn.1006-5725.2022.17.002.

HILL R, SANTHAKUMAR R, DEWEY W, et al . Fentanyl depression of respiration: comparison with heroin and morphine[J ] . Br J Pharmacol, 2020, 177(2): 254-266. DOI: 10.1111/bph.14860.

MOSS I R, BROWN K A, LAFERRIōRE A. Recurrent hypoxia in rats during development increases subsequent respiratory sensitivity to fentanyl[J]. Anesthesiology, 2006, 105(4): 715-718. DOI: 10.1097/00000542-200610000-00017.

NAIR A B, JACOB S. A simple practice guide for dose conversion between animals and human[J]. J Basic Clin Pharm, 2016, 7(2): 27-31. DOI: 10.4103/0976-0105.177703.

SCHOLZ J, STEINFATH M, SCHULZ M. Clinical pharmacokinetics of alfentanil, fentanyl and sufentanil. An update[J]. Clin Pharmacokinet, 1996, 31(4): 275-292. DOI: 10.2165/00003088-199631040-00004.

SUBRAMANIAN M, KURAWATTIMATH V, POCHA K, et al . Role of hepatic blood flow and metabolism in the pharmacokinetics of ten drugs in lean, aged and obese rats[J ] . Xenobiotica, 2014, 44(12): 1108-1116. DOI: 10.3109/00498254.2014.932470.

KANG H E, CHUNG H J, KIM H S, et al . Pharmacokinetic interaction between liquiritigenin (LQ) and DDB: increased glucuronidation of LQ in the liver possibly due to increased hepatic blood flow rate by DDB[J ] . Eur J Pharm Sci, 2010, 39(1/2/3): 181-189. DOI: 10.1016/j.ejps.2009.11.014.

NAEIJE R. Physiological adaptation of the cardiovascular system to high altitude[J]. Prog Cardiovasc Dis, 2010, 52(6): 456-466. DOI: 10.1016/j.pcad.2010.03.004.

BILO G, CARAVITA S, TORLASCO C, et al . Blood pressure at high altitude: physiology and clinical implications[J ] . Kardiol Pol, 2019, 77(6): 596-603. DOI: 10.33963/KP.14832.

SOLIMAN M M, ALDHAHRANI A, ALTHOBAITI F, et al . Characterization of the impacts of living at high altitude in taif: oxidative stress biomarker alterations and immunohistochemical changes[J ] . Curr Issues Mol Biol, 2022, 44(4): 1610-1625. DOI: 10.3390/cimb44040110.

CARMELIET P, JAIN R K. Molecular mechanisms and clinical applications of angiogenesis[J]. Nature, 2011, 473(7347): 298-307. DOI: 10.1038/nature10144.

TIPOE G L, LAU T Y, NANJI A A, et al . Expression and functions of vasoactive substances regulated by hypoxia-inducible factor-1 in chronic hypoxemia[J ] . Cardiovasc Hematol Agents Med Chem, 2006, 4(3): 199-218. DOI: 10.2174/187152506777698290.

FEIERMAN D E. Identification of cytochrome P450 3A1/2 as the major P450 isoform responsible for the metabolism of fentanyl by rat liver microsomes[J]. Anesth Analg, 1996, 82(5): 936-941. DOI: 10.1097/00000539-199605000-00008.

HORI Y, SHIMIZU Y, AIBA T. Altered hepatic drug-metabolizing activity in rats suffering from hypoxemia with experimentally induced acute lung impairment[J]. Xenobiotica, 2018, 48(6): 576-583. DOI: 10.1080/00498254.2017.1349969.

KURDI J, MAURICE H, EL-KADI A O, et al . Effect of hypoxia alone or combined with inflammation and 3-methylcholanthrene on hepatic cytochrome P450 in conscious rabbits[J ] . Br J Pharmacol, 1999, 128(2): 365-373. DOI: 10.1038/sj.bjp.0702795.

FRADETTE C, BLEAU A M, PICHETTE V, et al . Hypoxia-induced down-regulation of CYP1A1/1A2 and up-regulation of CYP3A6 involves serum mediators[J ] . Br J Pharmacol, 2002, 137(6): 881-891. DOI: 10.1038/sj.bjp.0704933.

李玉萍, 顾健腾, 陶国才, 等. 大鼠无肝状态小肠CYP3A1酶活性增强和mRNA表达增高及芬太尼肝外代谢[J]. 第三军医大学学报, 2008, 30(7): 606-609. DOI: 10.3321/j.issn:1000-5404.2008.07.016.

LI Y P, GU J T, TAO G C, et al . Activity and mRNA expression of cytochrome P450 and fentanyl metabolism in rat intestine in anhepatic phase[J ] . J Third Mil Med Univ, 2008, 30(7): 606-609. DOI: 10.3321/j.issn:1000-5404.2008.07.016.

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