基于超高效液相色谱-串联质谱法评价右美沙芬对大鼠CYP450酶活力的影响
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摘要
目的基于超高效液相色谱-串联质谱(UPLC-MS/MS)法同时测定大鼠血浆中5种探针药物(安非他酮、美托洛尔、咪达唑仑、非那西丁和甲苯磺丁脲),5种探针药物分别是细胞色素P450同工酶CYP2B6、CYP2D6、CYP3A4、CYP1A2和CYP2C9底物,评价右美沙芬对大鼠CYP450酶活性影响。方法将大鼠随机分成右美沙芬低剂量组36 mg/kg、高剂量组100 mg/kg、可待因组20 mg/kg和对照组4组。右美沙芬低剂量组、高剂量组灌胃给予右美沙芬30 d,可待因组灌胃给予可待因30 d,对照组灌胃给予生理盐水30 d。5种探针药物通过灌胃给予大鼠,用UPLCMS/MS测定血浆药物浓度。结果右美沙芬组和对照组对比结果中,安非他酮、美托洛尔、咪达唑仑、非那西丁和甲苯磺丁脲药代动力学差异均有统计学意义(P<0.05)。右美沙芬组中美托洛尔、甲苯磺丁脲AUC比对照组高(P<0.05),但安非他酮、咪达唑仑AUC比对照组低(P<0.05)。结论研究中,大鼠灌胃右美沙芬可能诱导大鼠CYP450亚型CYP2B6、CYP3A4、CYP1A2酶活性,可能抑制大鼠CYP2D6、CYP2C9酶活性。
Objective A specific ultra-performance liquid chromatography tandem mass spectrometry method( UPLC-MS/MS) has been described for the simultaneous determination of bupropion,metroprolol,midazolam,phenacetin and tolbutamide in rat plasma,which are the five probe drugs of the five cytochrome( CYP2B6,CYP2D6,CYP3A4,CYP1A2 and CYP2C9),to evaluate the effect of dextromethorphan on rat CYP450 enzyme activity. Methods The rats were randomly divided into low dextromethorphan dose group( 36 mg/kg),high dextromethorphan dose group( 100 mg/kg),codeine group( 20 mg/kg),and the control group. The dextromethorphan group rats were given 36 mg/kg and 100 mg/kg dextromethorphan by intragastric administration,codeine group were given 36 mg/kg codeine by intragastric administration,control group were given saline solution by intragastric administration. Five probe drugs were administered to rats by intragastric administration,and plasma drug concentrations were determined by UPLC-MS/MS. Results The dextromethorphan group was compared to control group,and there was statistical significance on the pharmacokinetic difference for bupropion,metroprolol,midazolam,phenacetin and tolbutamide( P < 0. 05). In dextromethorphan group,AUC of metoprolol and tolbutamide were higher than the control group,but AUC of bupropion and midazolam were lower than the control group( P < 0. 05). Conclusion Dextromethorphan may induce the activities of CYP2B6,CYP3A4 and CYP1 A2,and inhibit of CYP2D6 and CYP2C9 in rats.
Objective A specific ultra-performance liquid chromatography tandem mass spectrometry method( UPLC-MS/MS) has been described for the simultaneous determination of bupropion,metroprolol,midazolam,phenacetin and tolbutamide in rat plasma,which are the five probe drugs of the five cytochrome( CYP2B6,CYP2D6,CYP3A4,CYP1A2 and CYP2C9),to evaluate the effect of dextromethorphan on rat CYP450 enzyme activity. Methods The rats were randomly divided into low dextromethorphan dose group( 36 mg/kg),high dextromethorphan dose group( 100 mg/kg),codeine group( 20 mg/kg),and the control group. The dextromethorphan group rats were given 36 mg/kg and 100 mg/kg dextromethorphan by intragastric administration,codeine group were given 36 mg/kg codeine by intragastric administration,control group were given saline solution by intragastric administration. Five probe drugs were administered to rats by intragastric administration,and plasma drug concentrations were determined by UPLC-MS/MS. Results The dextromethorphan group was compared to control group,and there was statistical significance on the pharmacokinetic difference for bupropion,metroprolol,midazolam,phenacetin and tolbutamide( P < 0. 05). In dextromethorphan group,AUC of metoprolol and tolbutamide were higher than the control group,but AUC of bupropion and midazolam were lower than the control group( P < 0. 05). Conclusion Dextromethorphan may induce the activities of CYP2B6,CYP3A4 and CYP1 A2,and inhibit of CYP2D6 and CYP2C9 in rats.
引文
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[12]罗招凡,何嘉辉,方伟祯,等.广州地区心血管病患者CYP2C19~*1、CYP2C19~*17基因多态性对氯吡格雷疗效的影响[J].中国卫生检验杂志,2017,27(13):1831-1833,1837.
[13]赵永攀,石磊,李晋,等.CYP4F2和β-actin基因实时荧光定量PCR标准品质粒和标准曲线的构建[J].中国卫生检验杂志,2016,26(1):98-100.
[14]黄小慧,彭隆,许颖君,等.CYP2C19基因多态性对氯吡格雷抗血小板作用的影响[J].中国卫生检验杂志,2016,26(15):2129-2131.
[15]朱慧丹,周子晔,王贤亲,等.探针药物法评价辣椒碱对大鼠CYP450的影响[J].中国卫生检验杂志,2013,23(18):3474-3476.
[16]刘思洁,崔勇,姜楠,等.超高效液相色谱-串联质谱法测定植物源性食品中6种植物生长调节剂的残留量[J].中国卫生检验杂志,2016,26(4):500-503.
[17]冯靓,王军淋,张晶,等.超高效液相色谱-质谱联用法测定消毒产品中30种糖皮质激素[J].中国卫生检验杂志,2016,26(14):1987-1992.
[2]Manaboriboon B,Chomchai C.Dextromethorphan abuse in Thai adolescents:A report of two cases and review of literature[J].J Med Assoc Thai,2005,88(Suppl 8):242-245.
[3]Ramaswamy S.Topiramate in dextromethorphan abuse[J].Ann Clin Psychiatry,2015,27(4):302-303.
[4]Forrester MB.Dextromethorphan abuse in Texas,2000-2009[J].J Addict Dis,2011,30(3):243-247.
[5]Afshar M,Birnbaum D,Golden C.Review of dextromethorphan administration in 18 patients with subacute methotrexate central nervous system toxicity[J].Pediatric Neurol,2014,50(6):625-629.
[6]Nelson DR,Kamataki T,Waxman DJ,et al.The P450 superfamily:update on new sequences,gene mapping,accession numbers,early trivial names of enzymes,and nomenclature[J].DNA Cell Biol,1993,12(1):1-51.
[7]Zhang L,Reynolds KS,Zhao P,et al.Drug interactions evaluation:an integrated part of risk assessment of therapeutics[J].Toxicol App Pharmacol,2010,243(2):134-145.
[8]Breimer DD,Schellens JH.A'cocktail'strategy to assess in vivo oxidative drug metabolism in humans[J].Trends Pharmacol Sci,1990,11(6):223-225.
[9]Danton AC,Montastruc F,SOMMET A,et al.Importance of cytochrome P450(CYP450)in adverse drug reactions due to drugdrug interactions:a Pharmaco Vigilance study in France[J].Euro J Clin Pharmacol,2013,69(4):885-888.
[10]Wang ZY,Xu YY,Xu MZ,et al.Effect on CYP450 isoforms activity of rats after acute methomyl poisoning[J].Int J Clin Exp Med,2016,9(3):6490-6496.
[11]Wang XQ,Wang ZY,Zhang LJ,et al.Effect of paraquat on CYP450 isoforms activity of rats after intraperitoneal administration[J].Int J Clin Exp Med,2016,9(6):11619-11625.
[12]罗招凡,何嘉辉,方伟祯,等.广州地区心血管病患者CYP2C19~*1、CYP2C19~*17基因多态性对氯吡格雷疗效的影响[J].中国卫生检验杂志,2017,27(13):1831-1833,1837.
[13]赵永攀,石磊,李晋,等.CYP4F2和β-actin基因实时荧光定量PCR标准品质粒和标准曲线的构建[J].中国卫生检验杂志,2016,26(1):98-100.
[14]黄小慧,彭隆,许颖君,等.CYP2C19基因多态性对氯吡格雷抗血小板作用的影响[J].中国卫生检验杂志,2016,26(15):2129-2131.
[15]朱慧丹,周子晔,王贤亲,等.探针药物法评价辣椒碱对大鼠CYP450的影响[J].中国卫生检验杂志,2013,23(18):3474-3476.
[16]刘思洁,崔勇,姜楠,等.超高效液相色谱-串联质谱法测定植物源性食品中6种植物生长调节剂的残留量[J].中国卫生检验杂志,2016,26(4):500-503.
[17]冯靓,王军淋,张晶,等.超高效液相色谱-质谱联用法测定消毒产品中30种糖皮质激素[J].中国卫生检验杂志,2016,26(14):1987-1992.