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浙江大学学报(医学版)  2022, Vol. 51 Issue (4): 389-396    DOI: 10.3724/zdxbyxb-2022-0129
专题报道     
高原环境对格列喹酮药代动力学参数的影响
黄隆基,张晓静,罗林,牟宏芳,李文斌,王荣
中国人民解放军联勤保障部队第九四〇医院药剂科 全军高原医学实验室,甘肃 兰州 730050
Effects of high-altitude environment on pharmacokinetic parameters of gliquidone in rats
HUANG Longji,ZHANG Xiaojing,LUO Lin,MU Hongfang,LI Wenbin,WANG Rong
Department of Pharmacy, the 940th Hospital of Joint Logistics Support Force of Chinese People’s Liberation Army, Key Laboratory of the Plateau Medicine, Lanzhou 730050, China
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摘要:

目的:探讨高原低氧环境对格列喹酮体内药代动力学参数的影响。 方法:将12只Wistar雄性大鼠随机分为平原组与高原组,分别灌胃给予 6.3?mg/kg格列喹酮后采集血样。采用超快速液相色谱-串联质谱(UFLC-MS/MS)法测定大鼠血浆中格列喹酮浓度,并采用蛋白质印迹法测定大鼠肝组织中CYP2C9的表达。 结果:与平原组比较,高原组格列喹酮体内达峰血药浓度增加,吸收速率常数减小,消除速率常数增大,吸收半衰期延长,消除半衰期缩短,平均滞留时间缩短,表观分布容积减小(均 P<0.05)。蛋白质印迹法结果显示,高原组肝组织中代谢酶CYP2C9表达显著上调,约为平原组的1.98倍(分别为4.18±0.06和2.13±0.06,t=11.57, P<0.01)。 结论:高原低氧环境下,大鼠体内格列喹酮吸收减少、代谢加快,可能与大鼠肝组织中CYP2C9酶表达上调有关。

关键词: 高原低压性低氧超快速液相色谱-串联质谱格列喹酮药代动力学CYP2C9大鼠    
Abstract:

Objective: To investigate the effect of high-altitude hypoxia on the pharmacokinetics parameters of gliquidone. Methods: Twelve healthy male Wistar rats were randomly divided into plain group and high-altitude group with 6 rats in each group. Blood samples were collected after intragastric administration of gliquidone (6.3?mg/kg). Ultra-fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) was used to determine the concentration of gliquidone in rat plasma samples. And the expression of CYP2C9 in rat liver tissues was determined by Western blotting. Results: Compared with the plain group, the peak concentration of gliquidone in the high-altitude rats was significantly increased, the absorption rate constant was decreased, the elimination rate constant and the absorption half-life were increased, the elimination half-life was shortened, the mean residence time and apparent volume of distribution were decreased (all P<0.05). Western blotting showed that the expression of CYP2C9 was significantly up-regulated in the liver tissues of high altitude group rats, compared with the plain group (4.18 ±0.06vs. 2.13±0.06, t=11.57, P<0.01). Conclusion: Under the high-altitude hypoxia environment, the absorption of gliquidone in rats was reduced and the metabolism was accelerated in rats, which may be related to the up-regulation of CYP2C9 expression in liver tissues.

Key words: Plateau    Hypobaric hypoxia    Ultra-fast liquid chromatography-tandem mass spectrometry    Gliquidone    Pharmacokinetics    CYP2C9    Rats
收稿日期: 2022-04-01 出版日期: 2022-11-16
CLC:  R917  
基金资助: 国家科技重大专项(2018ZX09J18109-001); 国家自然科学基金(81673508,82173738)
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黄隆基
张晓静
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李文斌
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引用本文:

黄隆基,张晓静,罗林,牟宏芳,李文斌,王荣. 高原环境对格列喹酮药代动力学参数的影响[J]. 浙江大学学报(医学版), 2022, 51(4): 389-396.

HUANG Longji,ZHANG Xiaojing,LUO Lin,MU Hongfang,LI Wenbin,WANG Rong. Effects of high-altitude environment on pharmacokinetic parameters of gliquidone in rats. J Zhejiang Univ (Med Sci), 2022, 51(4): 389-396.

链接本文:

https://www.zjujournals.com/med/CN/10.3724/zdxbyxb-2022-0129        https://www.zjujournals.com/med/CN/Y2022/V51/I4/389

图1  大鼠血浆标本中格列喹酮和硝苯吡啶典型色谱图 A:空白血浆色谱图;B:加入 2 μg/mL格列喹酮对照品和内标 (1 μg/mL硝苯吡啶)的空白血浆色谱图;C:大鼠灌胃给予格列喹酮 2 h后的血浆色谱图.

格列喹酮浓度

(ng/mL)

n

日内

日间

精密度

准确度

精密度

准确度

5

6

4.95

100.63

3.81

99.87

500

6

1.23

100.23

1.01

101.07

3000

6

0.87

100.39

2.81

98.73

表1  大鼠血浆中格列喹酮的日内、日间的精密度及准 确度

格列喹酮浓度(ng/mL)

n

乙腈溶液

大鼠血浆

25?°C保存 12?h

–80?°C保存 10?d

–80?°C反复冻融3次

5

3

99.5±2.8

100.7±2.2

94.9±4.5

500

3

99.6 ±2.5

99.5±0.7

100.1±1.1

3000

3

100.3±0.4

100.2±0.3

100.0±0.8

表2  不同条件下格列喹酮的回收率
图2  平原组和高原组灌胃给予格列喹酮 (6.3 mg/kg)的平均血药浓度-时间曲线图 ( =6, ± )

组别

n

药时曲线下面积(h×μg/mL)

达峰时间(h)

达峰血药浓度(μg/mL)

吸收速率常数(1/h)

消除速率常数(1/h)

平原组

6

13.2±3.5

1.9±0.4

1.2±0.3

1.6±0.3

0.13±0.06

高原组

6

12.5±2.5

2.0±0.6

2.2±0.6

0.8±0.3

0.50±0.15

t

0.375

0.372

3.339

4.460

5.011

P

>0.05

>0.05

<0.01

<0.01

<0.01

组别

n

吸收半衰期(h)

消除半衰期(h)

平均滞留时间(h)

表观分布容积(L/kg)

清除率(mL·h -1·kg -1)

平原组

6

0.47±0.10

6.8±3.8

10.6±5.5

4.5±1.5

513±131

高原组

6

1.01±0.28

1.5±0.5

5.2±3.5

1.8±1.4

527±108

t

4.164

2.817

2.473

2.989

0.186

P

<0.01

<0.05

<0.05

<0.05

>0.05

表3  平原组和高原组血浆格列喹酮的药代动力学参数
图3  平原组和高原组大鼠肝组织中代谢酶CYP2C9的表达
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