UPLC-MS/MS法同时测定人血浆中辛伐他汀和辛伐他汀羟基酸的浓度

目的:建立UPLC-MS/MS法同时测定人血浆中辛伐他汀和辛伐他汀羟基酸的浓度。方法:血浆样品用甲基叔丁基醚提取,离心后取上清液氮气吹干,流动相复溶后进行UPLC-MS/MS测定。色谱柱:BEH C18(2.1 mm×50 mm,1.7μm);流动相:乙腈-0.01 mol.L-1醋酸铵(72∶28);流速:0.15 mL.min-1;柱温:40℃,进样量:8μL。电喷雾离子化(ESI),正离子模式多重反应选择离子检测(MRM),辛伐他汀、辛伐他汀羟基酸及内标洛伐他汀的检测离子对分别为:m/z 419→199,437→303,405→199。结果:血浆样品中辛伐他汀、辛伐他汀羟基酸线性范围分别为0.241～61.76 ng.mL-1(r=0.999,n=5)和0.344～88.16 ng.mL-1(r=0.997,n=5),日内、日间精密度(RSD)均小于15%,方法的平均回收率分别为100.6%和106.0%,血浆基质对血浆中的辛伐他汀和辛伐他汀羟基酸测定无干扰。结论:建立的UPLC-MS/MS法处理简单、灵敏、特异性高,定量准确,为辛伐他汀制剂的临床药代动力学研究提供了简便、准确的分析测定方法。     

高效液相-质谱串联法测定大鼠血浆中辛伐他汀及辛伐他汀酸的浓度

目的:建立HPLC-MS法测定大鼠血浆中辛伐他汀及其代谢物辛伐他汀酸的浓度。方法:血浆样本加入适量内标和醋酸铵缓冲液,以甲基叔丁基醚萃取后采用LC-MS进行分析。色谱柱采用Inertsil ODS-3柱(150 mm×2.1 mm,5.0μm);流动相由乙腈-2.5 mmol.L-1醋酸铵(含0.1%甲酸)(75∶25)组成,柱温35°C;流速0.3 mL.min-1;采用电喷雾离子源(ESI),以多反应监测方式(MRM)进行定量分析。辛伐他汀和内标洛伐他汀在正离子模式下定量分析离子对分别为m/z 419.2→m/z199.2和m/z 405.2→m/z 199.2;辛伐他汀酸和内标洛伐他汀酸在负离子模式下定量分析离子对分别为m/z 435.2→m/z319.2和m/z 421.4→m/z 319.2。结果:辛伐他汀和辛伐他汀酸在5.0～6 400 ng.mL-1内线性关系良好(r>0.999),最低定量限为0.1 ng.mL-1,提取回收率为87.91%～99.77%,日内、日间精密度均不高于8.95%。结论:该方法分析速度快、灵敏、准确,为临床进一步研究辛伐他汀提供了基础。     

UHPLC-MS/MS同时测定人血浆中辛伐他汀及其代谢产物

目的采用UHPLC-MS/MS同时测定人血浆中辛伐他汀及其代谢产物辛伐他汀酸,并研究辛伐他汀、辛伐他汀酸在人体内的药动学特征。方法血浆样品以乙醚萃取,采用UHPLC-MS/MS进行分析。色谱柱:Agilent ZORBAX SB-C18(100mm×2.1mm,3.5μm);乙腈-1mmol·L-1醋酸铵(甲酸调pH 4.5)为流动相梯度洗脱,流速:0.2 m L·min-1。采用电喷雾离子源(ESI),以多反应监测方式(MRM)进行定量分析。辛伐他汀和内标洛伐他汀在正离子模式下定量分析,离子对分别为m/z 419.4→199.3和m/z 405.3→199.3;辛伐他汀酸和内标洛伐他汀酸在负离子模式下定量分析,离子对分别为m/z435.5→115.2和m/z 421.4→101.2。结果辛伐他汀和辛伐他汀酸的线性范围均为0.2~50 ng·m L-1(r>0.99),最低定量限均为0.2 ng·m L-1,日内和日间精密度(RSD)均≤11.10%,提取回收率均≥63.71%。结论该方法专属性强、灵敏度高、重现性好,适用于辛伐他汀的药动学研究。     

HPLC法测定比格犬血浆中的辛伐他汀及辛伐他汀羟基酸

目的:建立血浆中辛伐他汀及其主要代谢活性成分辛伐他汀羟基酸的含量测定方法。方法:以洛伐他汀为内标物质,流动相采用甲醇-水-冰醋酸(74:26:0.5),检测波长为238nm,流速为1.0mL·min~(-1)。血浆样品采用乙腈沉淀蛋白处理。并测定了10只比格犬单剂量口服辛伐他汀自乳化胶囊和市售片后的血药浓度。结果:血浆中内源性物质对辛伐他汀及辛伐他汀羟基酸的测定无干扰;最低检出限辛伐他汀为0.5ng·mL~(-1),辛伐他汀羟基酸为0.75ng·mL~(-1);辛伐他汀羟基酸在2～100ng·mL~(-1)浓度范围内线性关系良好,r=0.9989,辛伐他汀在1～50ng·mL~(-1)浓度范围内线性关系良好,r=0.9993;绝对回收率为79.68%～95.3%,方法回收率为89.1%～95.3%;日内精密度 RSD≤2.9%、日间精密度 RSD≤4.6%。结论:本方法处理简单,无干扰,灵敏度高,适合测定生物样本中的辛伐他汀及辛伐他汀羟基酸。     

RP-HPLC法测定复方辛伐他汀烟酸缓释片中辛伐他汀的含量

目的采用RP-HPLC法,建立复方辛伐他汀烟酸缓释片中辛伐他汀含量的测定方法。方法色谱条件:Welch-C18色谱柱(4.6mm×33mm,3μm),以乙腈-0.1%磷酸溶液(50∶50)为流动相A,0.1%磷酸的乙腈溶液为流动相B进行梯度洗脱,流速为3.0mL·min-1;检测波长为238nm。结果辛伐他汀在19.99～999.6μg·mL-1范围内线性关系良好(r=0.9999),平均回收率为99.7%,(RSD=0.45%),定量限为27ng。结论该方法简单易操作,准确度好,专属性强,可用于辛伐他汀的含量测定。     

LC-MS/MS测定人血浆中的辛伐他汀

目的建立测定人血浆中辛伐他汀的方法。方法采用LC-MS/MS法,血浆样品中加入内标洛伐他汀,经乙腈沉淀蛋白后,以正离子多反应监测(MRM)方式测试,用于定量的离子为m/z441.2→325.2(辛伐他汀)和m/z427.2→325.2(洛伐他汀)。色谱柱为Restek Allure C18(50 mm×2.1 mm,5μm),流动相为乙腈-0.5%甲酸水溶液(70:30)。结果血浆中辛伐他汀的线性范围为0.1-50.0 ng.ml-1,定量限为0.1 ng.ml-1,方法回收率为98%~102%,日内RSD<3.6%,日间RSD<5.6%。结论所建方法专属性好、灵敏度高,符合血浆样品测定的要求,适用于辛伐他汀的临床药物动力学研究。     

液相色谱-串联质谱法同时测定人血浆中辛伐他汀和辛伐他汀酸

目的:建立LC-MS/MS法测定人血浆中辛伐他汀和辛伐他汀酸。方法:血浆样本以乙醚-二氯甲烷(3∶2)液液萃取后,选用Inertsil ODS-SP色谱柱(75 mm×2.1 mm,3μm),以乙腈-1 mmol.L-1乙酸铵(pH 4.50)(75∶25)为流动相,流速为0.25 mL.min-1;选用API3200型三重四极杆串联质谱仪的多重反应监测(MRM)扫描方式进行监测,电喷雾离子化源,同一分析周期内正负离子扫描切换。辛伐他汀及其内标洛伐他汀采用正离子检测,选择监测离子反应分别为m/z 436.4→m/z199.3(辛伐他汀)和m/z 405.4→m/z 199.3(洛伐他汀);辛伐他汀酸及其内标洛伐他汀酸采用负离子检测,选择监测离子反应分别为m/z 435.3→m/z 115.0(辛伐他汀酸)和m/z 421.2→m/z 101.0(洛伐他汀酸)。结果:辛伐他汀、洛伐他汀、辛伐他汀酸、洛伐他汀酸的保留时间分别为2.78,2.33,1.47,1.38 min;血浆中辛伐他汀和辛伐他汀酸的线性范围均为0.100～15.0μg.L-1(r>0.9950),定量下限均为0.100μg.L-1;日内、日间精密度(RSD)均小于15%;准确度(RE)均在±15%的范围以内;辛伐他汀和辛伐他汀酸的平均提取回收率分别为(77.9±2.6)%和(86.1±6.1)%;平均基质效应因子分别为(95.3±4.5)%和(73.2±3.5)%;稳定性试验中,在各种贮存条件下血浆中辛伐他汀和辛伐他汀酸均较稳定。结论:该方法专属性强,灵敏度高,重现性好,适用于辛伐他汀临床药代动力学研究。     

液相色谱-电喷雾串联质谱法测定人血浆中辛伐他汀浓度

目的:建立液相色谱-电喷雾串联质谱联用测定人血浆中辛伐他汀浓度的方法。方法:色谱条件为 Discovery ODS C_(18)(2.1 mm×100 mm,3μm)色谱柱;流动相为乙腈-0.1%甲酸溶液(65:35,v/v);柱温30℃;流速0.2 mL·min~(-1);进样量5μL。质谱条件为电喷雾电离源(ESI),选择性检测定量离子为 m/z 441.3/325.0(辛伐他汀)和 m/z 427.2/325.0(洛伐他汀,内标)带正电荷的离子峰。样品用乙酸乙酯提取。结果:血浆中辛伐他汀浓度在0.20～20.0 ng·mL~(-1)内呈良好线性关系,r=0.9996。提取回收率为90.0%～92.4%(RSD 6.0%～14.9%),方法回收率在85%～115%之内,日内和日间精密度试验的RSD 均<15%,最低检测浓度为0.2 ng·mL~(-1)。结论:该测定方法经全面考察符合血浆样品的测定要求,可以应用于辛伐他汀的人体药动学研究和生物等效性评价。     

HPLC-MS/MS测定人体血浆和尿液中罗通定的浓度

目的 建立一种简便、灵敏的测定人体血浆和尿液中罗通定浓度的高效液相色谱串联质谱( HPLC-MS/MS)方法.方法 血浆、尿液样品分别采用乙腈沉淀处理后,进样分析.采用Agilent-ECLIPSE-C18柱(2.1mm×150 mm,5μm),以乙腈-0.2％甲酸溶液=85∶15为流动相,采用正离子,多反应监测方式测定样品浓度.检测离子为m/z356.3→192.3(罗通定)和m/z 285.0→193.0(地西泮,内标).结果 罗通定血浆及尿样均在2.5～1000 ng· mL-1与峰面积线性关系良好(r=0.999 4);最低定量浓度均为2.5 ng·mL-1.日内与日间RSD均＜10％,血浆样品回收率在91.4％～109.2％,尿样回收率在88.63％～115.8％.结论 本方法简便快速、灵敏准确,适用于罗通定在人体内的药物动力学研究.     

HPLC-MS/MS法测定人血浆中奥昔布宁和去乙基奥昔布宁的质量浓度

目的 建立HPLC-MS/MS法测定人血浆中奥昔布宁和去乙基奥昔布宁的质量浓度.方法 选用Waters-Atlantis dC18色谱柱,以0.01％甲酸溶液-乙腈为流动相进行梯度洗脱,采用正离子多反应监测方式测定样品质量浓度.用于定量分析的离子对分别为m／z358.2→142.2(奥昔布宁),m/z330.2→96.2(去乙基奥昔布宁),m/z268.2→152.2(奥昔布宁D10),m/z 335.2→101.2(去乙基奥昔布宁D5).结果 血浆样品中,奥昔布宁在0.05～25 ng·mL-1线性关系良好(r=0.996 5),最低定量浓度为0.05 ng·mL-1;去乙基奥昔布宁在0.05～25 ng·mL-1线性关系良好(r=0.998 5),最低定量浓度为0.05 ng· mL-1.两者日内与日间RSD均＜15％,提取回收率＞75％,且稳定性均较好.结论 本方法简便快速、灵敏准确、特异性强,适用于奥昔布宁和去乙基奥昔布宁的体内药物动力学研究.     

国家食品药品监督管理局国家药品标准修订——辛伐他汀滴丸

本品含辛伐他汀(C₂₅H₃₈O₅)应为标示量的90.0%~110.0%。     

辛伐他汀的合成

本方法对以洛伐他汀为原料合成辛伐他汀的反应进行了改进,通过水解,硅烷化,酰化,脱硅烷化得到辛伐他汀,总收率可达58.3%。本方法降低了生产成本,提高了收率,更适合于工业生产。     

Ezetimibe/Simvastatin

Ezetimibe/simvastatin (Inegy, Vytorin) therapy combines two lipid-lowering compounds with complementary mechanisms of action, thereby blocking the two sources of plasma cholesterol and improving lipid profiles. Thus, intestinal absorption of dietary cholesterol and related phytosterols is blocked by ezetimibe, with the biosynthesis of cholesterol in the liver inhibited by simvastatin.Developing management trends for primary hypercholesterolemia include the aggressive reduction of low-density lipoprotein cholesterol (LDL-C) to goals lower than previously considered appropriate, the targeting of lipid subfractions and atherogenic indices other than LDL-C alone, and the broader use of combination lipid-lowering therapy. In line with these trends, ezetimibe/simvastatin is an effective and generally well tolerated adjunct to dietary therapy for markedly reducing LDL-C levels, providing a 52% reduction with the recommended starting dosage. Furthermore, ezetimibe/simvastatin is formulated with variable doses of simvastatin (i.e. 10/10 mg, 10/20 mg, 10/40 mg, and 10/80 mg) and hence, the dosage may be adjusted to suit the individual patient's needs. As longer-term efficacy, tolerability, economic and outcome data accrue, ezetimibe/simvastatin will be positioned more definitively relative to existing and emerging lipid-lowering treatments. Currently, ezetimibe/simvastatin therapy represents a valuable novel option for the management of primary hypercholesterolemia across diverse patient populations and as an adjunct to other lipid-lowering treatments in those with homozygous familial hypercholesterolemia.     

Interactions of Human P-glycoprotein with Simvastatin, Simvastatin Acid, and Atorvastatin

PURPOSE: In this study, P-glycoprotein (P-gp) mediated efflux of simvastatin (SV), simvastatin acid (SVA), and atorvastatin (AVA) and inhibition of P-gp by SV, SVA, and AVA were evaluated to assess the role of P-gp in drug interactions. METHODS: P-gp mediated efflux of SV, SVA, and AVA was determined by directional transport across monolayers of LLC-PK1 cells and LLC-PK1 cells transfected with human MDR1. Inhibition of P-gp was evaluated by studying the vinblastine efflux in Caco-2 cells and in P-gp overexpressing KBV1 cells at concentrations of SV, SVA, and AVA up to 50 microM. RESULTS: Directional transport studies showed insignificant P-gp mediated efflux of SV, and moderate P-gp transport [2.4-3.8 and 3.0-6.4 higher Basolateral (B) to Apical (A) than A to B transport] for SVA and AVA, respectively. Inhibition studies did not show the same trend as the transport studies with SV and AVA inhibiting P-gp (IC50 -25-50 microM) but SVA not showing any inhibition of P-gp. CONCLUSIONS: The moderate level of P-gp mediated transport and low affinity of SV, SVA, and AVA for P-gp inhibition compared to systemic drug levels suggest that drug interactions due to competition for P-gp transport is unlikely to be a significant factor in adverse drug interactions. Moreover, the inconsistencies between P-gp inhibition studies and P-gp transport of SV, SVA, and AVA indicate that the inhibition studies are not a valid means to identify statins as Pgp substrates.     

Simvastatin: Multiple Sclerosis

This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to ude.uk@larenegj.     

辛伐他汀药理作用分析研究

目的 通过对辛伐他汀治疗高血脂疾病分析,研究辛伐他汀药理作用.方法 随机选择本院2010年2月至2012年2月高血脂症患者85名,分成A、B两组,A组52名患者为观察组,给予辛伐他汀治疗;B组33名患者为治疗组,给予美托洛尔治疗.结果 经治疗,A组患者总胆固醇水平、甘油三酯水平、LDL-C及HDL-C水平均明显低于B组患者,不良反应发生率低于B组.结论 辛伐他汀药物具有较好的调脂作用,不良反应发生率较低.