佐米曲普坦片及胶囊的人体生物等效性研究

目的:比较受试佐米曲普坦片和胶囊与阿斯利康公司生产的参比佐米曲普坦片在健康人体内的药代动力学过程,并评价其生物等效性.方法:24名健康男性志愿者按体重配对、随机三交叉单剂量口服佐米曲普坦 5 mg,用高效液相色谱质谱选择性离子检测的内标法,测定血浆中药物浓度.结果:单剂量口服佐米曲普坦参比制剂和2种受试制剂 5 mg 后,三者的主要药代动力学参数:参比制剂、受试片剂、受试胶囊的AUC0-14分别为46.13±15.41 ng·h·mL-1,45.94±17.56 ng·h·mL-1,45.73±15.24 ng·h·mL-1;AUC0-∞分别为48.30±15.93 ng·h·mL-1,47.85±18.22 ng·h·mL-1,47.91±16.10 ng·h·mL-1;cmax分别为8.84±2.86 ng·mL-1,8.90±3.23 ng·mL-1,8.42±2.53 ng·mL-1;tmax分别为2.2±1.4 h,2.3±1.0 h,2.7±1.2 h;t1/2(Kel)分别为2.92±0.62 h,2.85±0.61 h,2.88±0.38 h;MRT分别为4.94±0.72 h,4.88±0.67 h,4.97±0.54 h.由AUC0-14计算2种受试制剂相对生物利用度分别为99.6%±17.5%,100.8%±15.9%.结论:2种受试制剂与参比制剂生物等效.     

洛伐他汀胶囊在健康人体的生物等效性研究

目的:考察两种洛伐他汀胶囊在健康人体的生物等效性.方法:20名健康男性志愿者单剂量口服试验制剂或参比制剂,采用LC/MS/MS法测定全血中药物浓度,用DAS2.1软件计算药代动力学参数.结果:试验制剂和参比制剂的主要药代动力学参数如下:t1/2分别为(4.67±2.34),(5.30±2.62)h;tmax分别为(1.90±0.50),(2.13±0.39)h;Cmax分别为(8.37±0.84),(8.29±1.00)ng·mL-1;AUC0-t分别为(32.25±6.49),(32.71±7.59)ng.h·mL-1;AUC0-∞分别为(33.62±6.94),(34.71±8.62)ng·h·mL-1.试验制剂的相对生物利用度F=(99.60±8.30)%.结论:受试制剂和参比制剂具有生物等效性.     

进口与国产利培酮薄膜衣片在健康志愿者的生物等效性

目的 研究利培酮薄膜衣片(抗精神分裂症药)在健康志愿者的药代动力学和生物等效性.方法 23名健康男性志愿者随机交叉、单剂量口服受试制剂(进口)和参比制剂(国产)2 mg后,用HPLC-MS/MS测定血浆中利培酮及9-羟基利培酮浓度,计算主要药代动力学参数,评价2种制剂的生物等效性.结果 受试制剂和参比制剂的主要药代动力学参数,利培酮:AUC0～t分别为(94.76±82.93)和(103.05±117.71)ng·h·mL-1;AUC0～1分别为(96.72±84.52)和(105.19±119.36)ng·h·mL0-1;Cmax分别为(15.91±5.63)和(16.21±11.56)ng·mL-1;tmax分别为(1.14±0.73)和(1.15±0.54)h;t1/2分别为(7.32±5.94)和(7.44±6.50)h,受试制剂的相对生物利用度为(106.68±40.21)%.9-羟基利培酮:AUC0-96h分别为(268.56±85.20)和(279.64 ±117.86)ng·h·mL-1;AUC0-∞分别为(282.74±87.46)和(294.28±120.32)ng·h·mL-1;Cmax分别为(10.84±4.69)和(11.11±4.80)ng·mL-1;tmax分别为(3.35±2.32)和(4.48±2.76)h;t1/2分别为(23.18±3.26)和(23.12±4.31)h,受试制剂的相对生物利用度为(101.37±27.23)%.结论 2种制剂具有生物等效性.     

扎鲁司特胶囊在健康人体的生物等效性

目的评价扎鲁司特胶囊与扎鲁司特片(均平喘药)在健康人体内的生物等效性。方法 20名健康男性志愿受试者随机分为2组,用双周期自身交叉、单剂量口服扎鲁司特胶囊(受试制剂)和扎鲁司特片(参比制剂)各20 mg后,用HPLC/MS-MS法测定扎鲁司特的血浆浓度,并计算药代动力学参数。结果受试制剂和参比制剂的主要药代动力学参数:tmax分别为(1.50±0.76),(1.63±0.48)h;Cmax分别为(505.34±208.73),(449.62±191.80)ng·mL-1;t1/2分别为(7.60±4.87),(7.36±4.50)h;AUC0-48分别为(1362±534),(1260±581)ng·h·mL-1;AUC0-∞分别为(1371±537),(1268±588)ng·h·mL-1。受试制剂的相对生物利用度为(113.6±29.7)%。结论扎鲁司特胶囊与扎鲁司特片具有生物等效性。     

氯沙坦钾胶囊与片在健康人体的生物等效性

目的评价氯沙坦钾胶囊与片剂(抗高血压药)在健康人体的生物等效性。方法用随机交叉试验设计,20名健康志愿者分别单剂口服氯沙坦钾受试制剂和参比制剂50mg,测定其血药浓度并进行生物等效性的检验。结果受试制剂和参比制剂的Cmax分别为(317.42±217.05),(295.57±132.16)ng·mL-1;tmax分别为(1.17±0.67),(1.27±0.73)h;AUC0-t分别为(637.63±379.83),(591.05±300.77)ng·h·mL-1,2制剂比较无显著性差异。结论氯沙坦钾胶囊与氯沙坦钾片为生物等效性制剂。     

液相色谱-串联质谱法测定人血浆氯吡格雷浓度及其生物等效性评价

目的:建立液相色谱-串联质谱法(LC-MS/MS)测定人血浆中氯吡格雷的浓度,研究2种硫酸氢氯吡格雷片的人体药动学及相对生物利用度。方法:血浆样品中加入内标美利曲辛,经乙腈沉淀蛋白提取,采用液相色谱-串联质谱法。用建立的方法测定20例健康男性受试者单剂量口服硫酸氢氯吡格雷受试制剂或参比制剂后的血药浓度,求得药动学参数,并对2种制剂的生物等效性进行评价。结果:在0.02～20 ng·mL-1内呈良好的线性关系,方法回收率98.4%～103.2%,日内、日间RSD均小于15%。单次口服75 mg硫酸氢氯吡格雷受试制剂或参比制剂后的Cmax分别为(1.9±1.5)ng·mL-1和(1.8±1.1)ng·mL-1;tmax分别为(0.8±0.5)h和(1.0±0.8)h;t1/2分别为(3.4±1.6)h和(3.5±1.5)h;AUC(0-48)分别为(4.4±4.3)h·ng·mL-1和(4.4±4.6)h·ng·mL-1;AUC(0-∞)分别为(4.7±4.4)h·ng·mL-1和(4.7±4.7)h·ng·mL-1。受试制剂对参比制剂的相对生物利用度为(98.2±32.8)%。结论:该方法灵敏,无杂质干扰。测得的受试制剂与参比制剂的主要药动学参数之间无明显差异,表明2种制剂在人体内生物等效。     

两种米非司酮片人体生物等效性研究

目的:比较2种米非司酮制剂的人体生物等效性。方法:将24名健康女性志愿者随机交叉单剂量口服米非司酮片(受试制剂)与米非司酮片(参比制剂)50mg,采用LC-MS/MS法测定人血浆中米非司酮浓度,用BAPP2.2版软件和DAS2.1.1版软件计算药动学参数和生物利用度。结果:口服受试制剂与参比制剂后的人体药动学参数分别为Cmax(1405.70±380.50)和(1263.80±258.80)ng·h·mL-1,tmax(0.70±0.30)和(0.60±0.30)h,t1/2β(31.70±7.80)和(28.70±9.40)h,AUC0~120(17821.50±4316.90)和(17612.90±6667.40)ng·h·mL-1,AUC0~∞(19286.40±5024.80)和(19053.40±7742.30)ng·h·mL-1。受试制剂的相对生物利用度为114.60%,AUC0~96的90%置信区间在参比制剂的等效范围内。结论:2种米非司酮制剂生物利用度等效。     

奥美拉唑肠溶胶囊的人体药物动力学和生物等效性研究

目的 研究奥美拉唑肠溶胶囊在人体内药动学和生物等效性.方法 健康志愿者20名,随机双交叉单剂量口服通化神源药业有限公司研制的奥美拉唑肠溶胶囊(试验制剂)和海口康元制药有限公司生产的奥美拉唑肠溶胶囊(参比制剂),剂量分别为40 mg,剂间间隔为1周.分别于服药后12 h内多点抽取静脉血,用高效液相色谱(HPLC)法测定血浆中奥美拉唑肠溶胶囊的浓度.用DAS(Drug And Statistics,version 2.0)药动学程序计算相对生物利用度并评价两种制剂生物等效性.AUC0-12,AUC(0-inf)和Cmax经方差分析和双单侧t检验,Tmax进行秩和检验.结果 单剂量口服奥美拉唑肠溶胶囊试验和参比制剂后,血浆奥美拉唑的Cmax分别为(1 146.77±386.58)ng·mL-1和(1 138.93±360.90)ng·mL-1;Tmax分别为(2.40±0.53 )h和(2.28±0.44)h;AUC(0-12)分别为(4 853.61±1 960.52)ng·h·mL-1和(4743.06±1 740.71)ng·h·mL-1;AUC(0-inf)分别为(5 111.76±2 031.72)ng·h·mL-1和(4 942.71±1 833.39)ng·h·mL-1.AUC(0-12)的90%可信区间为94.6～106.3%,AUC(0-inf)的90%可信区间为96.5～107.2%,Cmax的90%可信区间为95.9～104.3%.结论 试验制剂与参比制剂的人体相对生物利用度为(101.32±14.90)%,试验制剂与参比制剂具有生物学等效性.     

黄豆苷元胶囊健康人体生物等效性研究

目的研究两种黄豆苷元胶囊在健康志愿受试者中的药动学和人体生物等效性.方法20名男性健康志愿者随机交叉单次口服黄豆苷元胶囊受试制剂和参比制剂各150 mg后,采用反相高效液相色谱法,测定血浆中黄豆苷元的浓度,采用Das 2.1程序计算其药动学参数,评价黄豆苷元胶囊的人体生物等效性.结果受试制剂和参比制剂的主要药动学参数分别为t1/2(3.35 ±1.20)和(3.39±1.46)h;C…(150.8 ±30.5)和(154.6±31.1)ng·mL-1;Tmax(1.04 4-0.55)和(1.30 ±0.76)h;AUC0-l(474 ±85)和(486 ±114)ng·h·mL-l.以AUCo-l计算,与参比制剂相比受试制剂中黄豆苷元的平均相对生物利用度为(99.4 ±13.1)%.结论两种黄豆苷元胶囊具有生物等效性.     

多潘立酮口腔崩解片在健康人体的药动学和生物等效性

目的:建立液-质联用测定人血浆中多潘立酮的浓度,研究多潘立酮口腔崩解片与多潘立酮片的人体药动学及相对生物利用度。方法:血浆样品中加入内标盐酸苯海拉明,经甲醇沉淀蛋白,采用液-质联用测定。用建立的方法测定18例男性健康志愿者单剂量口服受试制剂(多潘立酮口腔崩解片)或参比制剂(多潘立酮片)后的血药浓度,求得药动学参数,并对2种制剂的生物等效性进行评价。结果:在0.100～50 ng·mL-1内呈良好的线性关系,方法回收率79.2%～87.8%,日内、日间RSD均小于15%。单次口服10 mg受试制剂或参比制剂后的Cmax分别为(20.5±7.6)和(15.8±6.1)ng·mL-1;tmax分别为(0.79±0.21)和(0.68±0.31)h;t1/2分别为(9.92±2.02)和(9.50±1.61)h;AUC(0-36)分别为(84.3±26.2)和(71.0±15.0)h·ng·mL-1;AUC(0-∞)分别为(89.8±28.2)和(74.6±16.4)h·ng·mL-1。受试制剂对参比制剂的相对生物利用度为(113.5±10.3)%。结论:该方法灵敏,无杂质干扰。测得的受试制剂与参比制剂的主要药动学参数之间无明显差异,表明2种制剂在人体内生物等效。     

HPLC法测定血脂康胶囊中洛伐他汀和洛伐他汀酸的含量

目的:建立血脂康胶囊中的洛伐他汀和洛伐他汀酸HPLC定量分析方法.方法:利用HPLC法,采用YMC-C 18柱(150 mm×4.6mm,4μm),流动相为甲醇:10 mmol·L-1甲酸铵-0.2％甲酸水溶液(73:27),流速为1.0 ml·min -1,检测波长为237 nm.结果:洛伐他汀的线性范围为1.649～9.891 μg(r =1.0000),平均回收率为98.5％(RSD =2.31％,n=6);洛伐他汀酸的线性范围为0.221～1.327μg(r=1.000 0),平均回收率为96.3％(RSD=2.03％,n=6).结论:本方法专属性强、结果准确、简便可行,可用于血脂康胶囊及其它相关天然他汀类药物的质量控制.     

发酵液中洛伐他汀及其开环酸的HPLC测定

建立了HPLC法同时测定发酵液中洛伐他汀及其开环酸的含量。采用C8柱，流动相为10mmol／L磷酸-乙腈（40：60），检测波长238nm。洛伐他汀及其开环酸分别在0．012-0．096mg／ml和0．01-0．08mg／ml范围内线性关系良好，平均回收率分别为99．8％和98．7％。     

RP-HPLC测定洛伐他汀及胶囊的含量

目的 采用HPLC测定洛伐他汀及其胶囊的含量.方法 色谱柱为Agela C18柱(250 mm×4.6 mm,5μm),流动相为乙腈-0.01%磷酸(60:40),流速1.0 ml·min-1.检测波长238 nm.结果 洛伐他汀的线性方程为:A=5.980×104+2.910×104C(r=0.9999),线性范围4.88～305.00 μg·ml-1,胶囊平均回收率为100.20%,RSD=0.24%(n=9).结论 所建方法准确、重复性好、操作简单,可有效地控制药品质量.     

反相高效液相色谱法测定洛伐他汀胶囊的含量和有关物质

目的建立测定洛伐他汀胶囊含量及有关物质的反相高效液相色谱法。方法采用HypersilC18柱（250mm×4．6mm,10μm）,以乙腈一磷酸盐缓冲液（pH=4．0）-甲醇（5：3：1）为流动相,检测波长为238nm。结果洛伐他汀质量浓度在80．63～322．53μg／mL范围与峰面积呈良好线性关系（r=0．9997,n=7）,规格为10mg和20mg洛伐他汀的平均回收率分别为99．56％和99．67％,RSD分别为0．42％和0．83％（n=9）。洛伐他汀及其有关物质得到基线分离,方法的最低检测量为0．2ng,控制总杂质量不得超过2．0％。结论该法测定洛伐他汀胶裳的含量及有关物质,方法简便、快速、结果准确,专属性好,适用于洛伐他汀胶囊及其制剂的质量控制。     

国家食品药品监督管理局国家药品标准修订——洛伐他汀分散片

本品含洛伐他汀(C₂₄H₃₆O₅)应为标示量的90.0%~110.0%     

Lovastatin for hypercholesterolemia

Lovastatin is the first 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor approved for the treatment of primary hypercholesterolemia. It is indicated as adjunctive therapy to dietary control and should be initiated at 20 mg/d in the evening. With higher dosages, twice-daily dosing is preferred, particularly when the dosage reaches the maximum recommended 80 mg/d. Compared with other drugs available, lovastatin has been shown to have good efficacy and a low incidence of side effects. Limited pharmacokinetic information available from the manufacturer reports absorption approximately 30 percent, protein binding greater than 95 percent, and a dual pathway for elimination through both urine (10 percent) and feces (83 percent). The drug has been clinically tested versus placebo and in combination with other cholesterol-lowering drugs. Lovastatin is effective in lowering total cholesterol and low-density lipoprotein cholesterol by 25-30 percent, with nonfamilial (hypercholesterolemic) patients responding better than those with the familial form of the disease. One percent of lovastatin patients have discontinued therapy because of intolerable side effects. The most common complaints are flatulence and diarrhea; more severe abnormalities include elevation of liver enzymes and an unclear propensity for producing lens opacities. The monthly cost to a patient taking 20 mg/d is approximately $44. Although the drug should be added to hospital formularies, long-term safety experience and competition from other HMG-CoA reductase inhibitors will determine lovastatin's final therapeutic role.     

Lovastatin induces platelet apoptosis

Statins are widely used in the prevention of atherosclerosis and treatment of coronary artery disease because of pleiotropic effects on thrombosis. Thrombocytopenia and hemorrhage occurred in some statin-treated patients, but the reason remains unclear. In the current study, we show that lovastatin dose-dependently induces depolarization of mitochondrial inner transmembrane potential, leading to up-regulation of Bak, down-regulation of Bcl-X_L, and activation of caspase-3/8/9. Lovastatin treatment did not increase the surface expression of P-selectin or PAC-1 binding but led to strongly reduced collagen- and thrombin-induced platelet aggregation. The integrin α_IIbβ₃ antagonist, RGDS, inhibited lovastatin-induced apoptosis in both human platelets and Chinese hamster ovary (CHO) cells stably expressing integrin α_IIbβ₃. The number of circulating platelets in mice was significantly reduced after intraperitoneal injections with lovastatin. Taken together, these data indicate that lovastatin induced caspase-dependent platelet apoptosis. Lovastatin does not incur platelet activation, whereas impairs platelet function and reduces circulating platelets in vivo, suggesting the possible pathogenesis of thrombocytopenia and hemorrhage in patients treated with statins.     

洛伐他汀在巴马小型香猪体内毒动学研究

目的研究洛伐他汀在巴马小型香猪体内的毒动学特点。方法选健康雄性巴马小型香猪4头,灌胃给予洛伐他汀1.25 g.kg-1,采用反相高效液相色谱法测定不同时间的血药浓度,用3P97实用药动学程序计算毒动学参数。结果洛伐他汀分布相半衰期t1/2(α)为0.807 h,消除相半衰期t1/2(β)为18.376 h,浓度-时间曲线下面积(AUC)为95.964μg.h.mL-1。结论洛伐他汀在巴马小型香猪体内毒动学行为符合具一级消除的二室血管外给药模型,在巴马小型香猪体内清除较快。     

Combination Therapy with Low-Dose Lovastatin and Niacin Is as Effective as Higher-Dose Lovastatin

Study Objectives . To determine if low-dose lovastatin in combination with niacin causes a greater percentage reduction in low-density lipoprotein (LDL) cholesterol than lovastatin alone, and to determine if the combination increases the risk of serious adverse effects. Design . Prospective, randomized, open-label, clinical trial. Setting . Family medicine clinic of a university-affiliated hospital. Patients . Patients with fasting LDL cholesterol concentrations of at least 150 mg/dl after 4 weeks of dietary stabilization and washout of any cholesterol-lowering drugs. Interventions . Twenty-eight patients received lovastatin 20 mg/day for 4 weeks after dietary stabilization and washout. If LDL cholesterol remained above 130 mg/dl (100 mg/dl in patients with coronary artery disease), they were randomized to receive either lovastatin 40 mg/day or a combination of lovastatin 20 mg/day and niacin 500 mg 3 times/day. Measurements and Main Results . There was no difference in actual or percentage reductions of LDL cholesterol, total cholesterol, and triglycerides between the groups. A greater increase in high-density lipoprotein (HDL) cholesterol occurred with combination therapy (p=0.024). There was no difference in liver function tests, glucose, or uric acid between the therapies. Based on drug-acquisition cost, combination therapy is approximately 40% less expensive than monotherapy. Conclusion . Low-dose niacin plus low-dose lovastatin was as effective as higher-dose lovastatin in lowering total cholesterol, LDL cholesterol, and triglyceride levels. The combination may offer benefit in raising HDL cholesterol levels.