Please wait a minute...
浙江大学学报（医学版）
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
 全文: PDF(1349 KB)   HTML( 27 )
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）
服务　　
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章　　
黄隆基
张晓静
罗林
牟宏芳
李文斌
王荣

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    或    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值

—

0.375

0.372

3.339

4.460

5.011

P值

—

>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值

—

4.164

2.817

2.473

2.989

0.186

P值

—

<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
1 霍　妍, 赵安鹏, 李　雪, 等. 急性高原病的动物模型研究现状[J]. 中国药理学通报, 2021, 37(1): 26-30
HUO Yan, ZHAO Anpeng, LI Xue, et al. Animal models of acute plateau disease[J]. Chinese Pharmacological Bulletin, 2021, 37(1): 26-30. (in Chinese)
2 张娟玲, 李向阳. 高原低氧影响药物代谢的研究进展[J]. 药学学报, 2015, 50(9): 1073-1079
ZHANG Juanling, LI Xiangyang. A review of drug metabolism under hypoxia environment at high altitude[J]. Acta Pharmaceutica Sinica, 2015, 50(9): 1073-1079. (in Chinese)
3 袁雪纯, 向大伟, 敏　琼, 等. 急进高原缺氧对大鼠肝脏孕烷X受体表达的影响[J]. 浙江大学学报(医学版), 2019, 48(6): 603-608
YUAN Xuechun, XIANG Dawei, MIN Qiong, et al. Effects of acute hypoxia on expression of pregnane X receptor in liver tissues of rats exposed to high altitude[J]. Journal of Zhejiang University (Medi-cal Sciences), 2019, 48(6): 603-608. (in Chinese)
4 王　昌, 贾正平, 李文斌, 等. UFLC-MS/MS法测定急进高原前后大鼠体内左氧氟沙星含量及其药代动力学差异[J]. 华中科技大学学报(医学版), 2017, 46(2): 160-164
WANG Chang, JIA Zhengping, LI Wenbin, et al. UFLC-MS/MS assay for pharmacokinetics of levofloxacin in rats after acute ascent to high altitude[J]. Journal of Huazhong University of Science and Technology (Medical Sciences), 2017, 46(2): 160-164. (in Chinese)
5 ZHOU X , NIAN Y , QIAO Y , et al.Hypoxia plays a key role in the pharmacokinetic changes of drugs at high altitude[J]Curr Drug Metab, 2018, 19( 11): 960-969.
doi: 10.2174/1389200219666180529112913
6 李文斌, 王　荣, 谢　华, 等. 急进4010米高原对呋塞米药代动力学参数的影响[J]. 药学学报, 2012, 47(12): 1718-1721
LI Wenbin, WANG Rong, XIE Hua, et al. Effects on the pharmacokinetics offurosemide after acute exposure to high altitude at 4010 meters in rats[J]. Acta Pharmaceutica Sinica, 2012, 47(12): 1718-1721. (in Chinese)
7 ASSOCIATION A D. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes—— 2021[J]. Diabetes Care, 2021, 44(Suppl 1): S15-S33
8 徐亚明, 沈海欢. 格列喹酮联合阿卡波糖治疗老年糖尿病的疗效观察[J]. 糖尿病新世界, 2017, 20(7): 96-97
XU Yaming, SHEN Haihuan. Efficacy of gliclazone combined with acarbose in the treatment of senile diabetes mellitus[J]. Diabetes New World, 2017, 20(7): 96-97. (in Chinese)
9 XU L , LI Y , DAI Y , et al.Natural products for the treatment of type 2 diabetes mellitus: pharmacology and mechanisms[J]Pharmacol Res, 2018, 451-465.
doi: 10.1016/j.phrs.2018.01.015
10 MALAISSE W J . Gliquidone contributes to improvement of type 2 diabetes mellitus management[J]Drugs R D, 2006, 7( 6): 331-337.
doi: 10.2165/00126839-200607060-00002
11 马杜娟, 罗　玮, 蒋艳萍, 等. 高原地区肥胖与2型糖尿病及其微血管并发症的研究进展[J]. 青海医药杂志, 2021, 51(3): 61-64
MA Dujuan, LUO Wei, JIANG Yanping, et al. Research progress on obesity, type 2 diabetes and its microvascular complications at high altitude[J]. Qing-hai Medical Journal, 2021, 51(3): 61-64. (in Chinese)
12 于海云, 刘晶晶, 王红红. 反相高效液相色谱法测定格列喹酮片含量[J]. 中国药品标准, 2017, 18(4): 279-282
YU Haiyun, LIU Jingjing, WANG Honghong. HPLC determination of the content of gliguidone tablets[J]. Drug Standards of China, 2017, 18(4): 279-282. (in Chinese)
13 ABE M , OKADA K , SOMA M . Antidiabetic agents in patients with chronic kidney disease and end-stage renal disease on dialysis: metabolism and clinical practice[J]Curr Drug Metab, 2011, 12( 1): 57-69.
doi: 10.2174/138920011794520053
14 WARING R H . Cytochrome P450: genotype to phenotype[J]Xenobiotica, 2020, 50( 1): 9-18.
doi: 10.1080/00498254.2019.1648911
15 HE F , LI Y , ZENG C , et al.Contribution of cytochrome P450 isoforms to gliquidone metabolism in rats and human[J]Xenobiotica, 2014, 44( 3): 229-234.
doi: 10.3109/00498254.2013.831957
16 MANIKANDAN P , NAGINI S . Cytochrome P450 structure, function and clinical significance: a review[J]Curr Drug Targets, 2018, 19( 1): 38-54.
doi: 10.2174/1389450118666170125144557
17 KUDZI W , DODOO A N , MILLS J J . Characterisation of CYP2C8, CYP2C9 and CYP2C19 polymorphisms in a Ghanaian population[J]BMC Med Genet, 2009, 10( 1): 124.
doi: 10.1186/1471-2350-10-124
18 RENDIC S . Summary of information on human CYP enzymes: human P450 metabolism data[J]Drug Metab Rev, 2002, 34( 1-2): 83-448.
doi: 10.1081/DMR-120001392
19 HIRATSUKA M . Genetic polymorphisms and in vitro functional characterization of CYP2C8, CYP2C9, and CYP2C19 allelic variants[J]Biol Pharmaceutical Bull, 2016, 39( 11): 1748-1759.
doi: 10.1248/bpb.b16-00605
20 HOLSTEIN A , HAHN M , PATZER O , et al.Impact of clinical factors and CYP2C9 variants for the risk of severe sulfonylurea-induced hypoglycemia[J]Eur J Clin Pharmacol, 2011, 67( 5): 471-476.
doi: 10.1007/s00228-010-0976-1
21 LUO B , WANG R , LI W , et al.Pharmacokinetic changes of norfloxacin based on expression of MRP2 after acute exposure to high altitude at 4300 m[J]Biomed Pharmacother, 2017, 1078-1085.
doi: 10.1016/j.biopha.2017.02.092
22 WANG R , SUN Y , YIN Q , et al.The effects of metronidazole on cytochrome P450 activity and Expression in rats after acute exposure to high altitude of 4300 m[J]Biomed Pharmacother, 2017, 296-302.
doi: 10.1016/j.biopha.2016.11.024
23 白　雪, 刘贵琴, 杨建鑫, 等. 肠道菌群介导高原低氧对药物代谢的调节[J]. 药学学报, 2021, 56(10): 2787-2796
BAI Xue, LIU Guiqin, YANG Jianxin, et al. The effect of high-altitude hypoxia on drug metabolism is mediated by gut microbiota [J]. Acta Pharmaceutica Sinica, 2021, 56(10): 2787-2796. (in Chinese)
24 FRADETTE C , BATONGA J , TENG S , et al.Animal models of acute moderate hypoxia are associated with a down-regulation of CYP1A1, 1A2, 2B4, 2C5, and 2C16 and up-regulation of CYP3A6 and P-glycoprotein in liver[J]Drug Metab Dispos, 2007, 35( 5): 765-771.
doi: 10.1124/dmd.106.013508
25 张娟玲. 高原低氧对药物代谢酶CYP1A2、CYP2C11、CYP2C22和CYP3A1活性和表达的影响[D]. 西宁: 青海大学, 2017
ZHANG Juanling. The activity and expression of CYP1A2, CYP2C11, CYP2C22 and CYP3A1 in rats after exposure to high altitude hypoxia[D]. Xining: Qinghai University, 2017. (in Chinese)
26 段雅彬, 朱俊博, 杨建鑫, 等. microRNA介导低氧对药物代谢酶和转运体的调控[J]. 药学学报, 2021, 56(1): 50-60
DUAN Yabin, ZHU Junbo, YANG Jianxin, et al. Effect of hypoxia on drug metabolizing enzymes and transporters and the role of microRNA[J]. Acta Pharmaceutica Sinica, 2021, 56(1): 50-60. (in Chinese)
27 敏　琼, 封士兰, 鹿　辉, 等. 低氧对药物代谢酶和转运体的影响及其调控机制[J]. 生理学报, 2019, 71(2): 336-342
MIN Qiong, FENG Shilan, LU Hui, et al. Modulation of drug-metabolizing enzymes and transporters under hypoxia environment[J]. Acta Physiologica Sinica, 2019, 71(2): 336-342. (in Chinese)
[1] 张轶雯,盛孔胜,宋飞凤,潘宗富,邹小舟,刘宇佳,黄萍. 清肺口服液在特发性肺纤维化中的治疗作用及网络药理学研究[J]. 浙江大学学报（医学版）, 2022, 51(1): 53-61.
[2] 曹秋丽,黎小炜,禤秀萍,黄松,谢雪梅. 宫内发育迟缓出生后追赶生长大鼠脂肪组织LRP6/β-catenin通路表达变化[J]. 浙江大学学报（医学版）, 2021, 50(6): 755-761.
[3] 李敏,朱再满,叶政,王惠,刘克宇. 海马CA3区θ~γ神经振荡模拟刺激对大鼠空间认知能力的影响[J]. 浙江大学学报（医学版）, 2021, 50(6): 762-769.
[4] 邹蓓蕾,田贻婷,石志群,张汝学,马慧萍. 雪莲有效成分对高原缺氧小鼠心脑组织的保护作用[J]. 浙江大学学报（医学版）, 2021, 50(5): 568-574.
[5] 邹玉林,崔秀明,向巧,郭敏,梁应忠,曲媛,杨晓艳. 酱头抗胃溃疡的作用及机制研究[J]. 浙江大学学报（医学版）, 2021, 50(5): 561-567.
[6] 苗路伟,赵彤,高迎春,景临林,黄琼,马慧萍. 7-羟乙基白杨素对低压性缺氧大鼠运动性疲劳具有保护作用[J]. 浙江大学学报（医学版）, 2021, 50(5): 575-581.
[7] 刘俊霞,赵桂桂,牛岩,甘婷,闫震宇,张雅素. 电针疗法对脑卒中大鼠肢体痉挛的改善作用[J]. 浙江大学学报（医学版）, 2021, 50(3): 361-368.
[8] 李扬,李伟光,冯泽国,宋杰,张成岗,黄连军,宋燕平. 手术创伤及多次丙泊酚麻醉对发育期大鼠神经发育和认知功能的影响[J]. 浙江大学学报（医学版）, 2021, 50(3): 290-297.
[9] 张玉荣,王瑞忠,王莉,陈蕊. 母婴分离诱导子代抑郁大鼠肠道氨基酸代谢失调[J]. 浙江大学学报（医学版）, 2021, 50(3): 298-304.
[10] 张冉,刘云,张翠,马梦尧,李曙,洪云. 盐诱导激酶2对脑缺血再灌注大鼠脑组织能量代谢的影响[J]. 浙江大学学报（医学版）, 2021, 50(3): 352-360.
[11] 郑心甜,甘海燕,李琳,胡小伟,方燕,储利胜. 黄芪甲苷通过促进小胶质细胞/巨噬细胞M2型极化抑制大鼠脑缺血后炎症反应[J]. 浙江大学学报（医学版）, 2020, 49(6): 679-686.
[12] 诸葛陆杰,方燕,金华倩,李琳,杨琰,胡小伟,储利胜. 补阳还五汤上调miR-199a-5p表达促进脑缺血大鼠神经发生和血管生成[J]. 浙江大学学报（医学版）, 2020, 49(6): 687-696.
[13] 袁雪纯,向大伟,敏琼,丁怡丹,赵安鹏,王荣. 急进高原缺氧对大鼠肝脏孕烷X受体表达的影响[J]. 浙江大学学报（医学版）, 2019, 48(6): 603-608.
[14] 丁怡丹,李文斌,王荣,张建春. 高原低氧对血脑屏障结构及其药物通透性影响的研究进展[J]. 浙江大学学报（医学版）, 2019, 48(6): 668-673.
[15] 李雪,李文斌,封士兰,王荣. 血红蛋白在高原低氧适应中的机制研究进展[J]. 浙江大学学报（医学版）, 2019, 48(6): 674-681.