【摘要】：目的建立液相色譜-串聯質譜法(LC-MS/MS)同時測定非那西丁(PN)、咪達唑侖(MDZ)在大鼠血液中的含量。方法大鼠隨機被分為PN組、MDZ組和PN-MDZ合用組(均n=6),分別尾靜脈注射PN、MDZ及PN和MDZ混合探針藥物,劑量均為1 mg·kg-1。于指定時間眼眶采集血樣,以苯海拉明為內標,采用LC-MS/MS測定大鼠血漿中探針藥物及其代謝產物的濃度。色譜柱為Kinetex XB-C18柱(100 mm×3.0 mm,2.6μm),流動相為甲醇∶0.025%甲酸水,進行梯度洗脫。電噴霧離子源,以多反應離子監(jiān)測方法進行正離子掃描,PN和其代謝產物醋氨酚(Ace),MDZ和其代謝產物1-羥基咪達唑侖(1-OH-MDZ)及苯海拉明離子對分別為m/z 180.2→110.0,m/z 152.2→110.1,m/z 326.2→291.2,m/z 342.2→324.2和m/z 256.3→167.2。結果PN、Ace、MDZ和1-OH-MDZ線性范圍分別為:4.288~21 440 ng·m L-1、1.038~5 190 ng·m L-1、4.664~11 660 ng·m L-1、0.01~50 ng·m L-1;回收率、穩(wěn)定性和日內、日間精密度均符合生物樣品分析要求;PN和MDZ單用與合用前后藥動學參數無顯著差異(P0.05)。PN單用和與MDZ合用后t1/2分別為(0.44±0.15)、(0.42±0.08)h,ρmax分別為(9.35±1.58)、(10.17±0.76)μg·m L-1,AUC0-6 h分別為(4.21±0.63)、(4.90±0.42)μg·h·m L-1;MDZ單用和與PN合用后t1/2分別為(0.64±0.09)、(0.68±0.05)h,ρmax分別為(3.48±0.51)、(3.01±0.64)μg·m L-1,AUC0-6 h分別為(2.58±0.41)、(2.08±0.29)μg·h·m L-1。結論建立的測定方法可用于PN、MDZ以及其代謝產物的藥動學研究,并證明PN、MDZ在大鼠體內基本沒有代謝的相互作用。
[Abstract]:Objective to establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of fenacetin (PN), midazolam (MDZ) in rat blood. Methods the rats were randomly divided into three groups: PN group, MDZ group and PN-MDZ combination group (all n = 6). PN,MDZ and PN and MDZ mixed probe drugs were injected intravenously into tail vein at a dose of 1 mg kg-1.. Blood samples were collected from the orbit at the specified time and diphenhydramine was used as the internal standard to determine the concentration of probe drugs and their metabolites in rat plasma by LC-MS/MS. The chromatographic column was Kinetex XB-C18 column (100 mm 脳 3.0 mm, 2.6 渭 m), the mobile phase was methanol: 0.025% formic acid water, and gradient elution was carried out. Electrospray ion source, positive ion scanning with multi-reaction ion monitoring method, PN and its metabolite acetaminophen (Ace), MDZ and its metabolites, 1-hydroxymidazolam (1-OH-MDZ) and diphenhydramine ion pairs were 180.2, 152.2, 326.2 and 291.2, respectively. M\ x {5ee5} z 342.2 / 324.2 and m\ {# * $} z 256.3 / 167.2. Results the linear ranges of PN,Ace,MDZ and 1-OH-MDZ were 4.288 ~ 21,440 ng 路mL ~ (- 1), 1.038 ~ 5 190 ng 路mL ~ (- 1), 4.664 ~ 11.660 ng 路mL ~ (- 1), 0.01 ~ 50 ng 路mL ~ (- 1), respectively. The recovery, stability, intra-day and inter-day precision all meet the requirements of biological sample analysis. There was no significant difference in pharmacokinetic parameters before and after combination of PN and MDZ (P0.05). After PN alone and combined with MDZ, t _ 1-max _ 2 was (0.44 鹵0.15), (0.42 鹵0.08 h and 蟻 max was (9.35 鹵1.58) h, respectively. (10.17 鹵0.76) 渭 g 路mL ~ (- 1) and (4.21 鹵0.63), (4.90 鹵0.42) 渭 g 路h 路mL ~ (- 1) for 6 h, and (4.21 鹵0.63) 渭 g 路h 路mL ~ (- 1) for 6 h, respectively. T _ 1 ~ (2), 蟻 _ (max) and AUC _ (0) were (0.64 鹵0.09), (0.68 鹵0.05h, (3.48 鹵0.51), (3.01 鹵0.64) 渭 g 路mL ~ (- 1) and (2.58 鹵0.41) 渭 g 路mL ~ (- 1) for MDZ alone and combined with PN, respectively. (2.08 鹵0.29) 渭 g 路h 路mL. Conclusion the established method can be used to study the pharmacokinetics of PN,MDZ and its metabolites, and it is proved that there is no metabolic interaction between PN,MDZ and its metabolites in rats.
【作者單位】： 江西中醫(yī)學院現代中藥制劑教育部重點實驗室;成都中醫(yī)藥大學藥學院;
【基金】：國家自然科學基金資助項目(81060347) 國家留學基金委資助項目(留金法[2012]5031) 江西省青年科學學培養(yǎng)計劃項目(20122BCB23021) 江西省教育廳科學技術研究項目(GJJ13606)
【分類號】：R965

【共引文獻】

相關期刊論文 前10條

1 禮嵩;唐原君;何菁宇;葉曉嵐;楊鵬;李偉;范國榮;;注射用鹽酸頭孢他美對大鼠肝微粒體CYP1A2、CYP3A4和CYP2E1活性的影響[J];第二軍醫(yī)大學學報;2013年11期

2 王丹;張振清;阮金秀;;中藥對細胞色素P450誘導或抑制作用的影響因素[J];解放軍藥學學報;2008年03期

3 王亮;郭姣;石忠峰;江濤;;“Cocktail”探針藥物法的研究思路與應用[J];遼寧中醫(yī)藥大學學報;2010年11期

4 段雅彬;姚星辰;李向陽;;藏藥余甘子對大鼠CYP2C9活性的影響[J];中國民族民間醫(yī)藥;2014年11期

5 馮艷艷;李健;張德寧;劉萍;葛倩倩;呂建建;高保全;;三疣梭子蟹(Portunus trituberculatus)CYP2基因的cDNA克隆及表達分析[J];海洋與湖沼;2014年05期

6 鄭蓓蓓;;Cocktail法在中藥研究中的應用[J];內蒙古中醫(yī)藥;2014年31期

7 楊秀嶺;張志清;趙永紅;崔文寧;劉劍;;探針藥物法評價丁苯酞對大鼠體內CYP2C19酶活性的影響[J];河北醫(yī)科大學學報;2013年12期

8 袁靖;趙軍寧;李祖?zhèn)?;肝藥代謝酶研究方法及中藥影響的研究進展[J];四川中醫(yī);2007年06期

9 鐘育敏;吳文康;;中藥對細胞色素P450調控作用的研究進展[J];陜西中醫(yī);2011年02期

10 周昆;朱桃桃;張s，

本文編號：2463530