小檗碱对大鼠口服阿托伐他汀钙药代动力学的影响

目的研究小檗碱对大鼠口服阿托伐他汀钙药代动力学的影响,为临床联合用药提供参考依据。方法大鼠随机分为5组,单次阿托伐他汀钙组(A组)、单次小剂量小檗碱+阿托伐他汀钙组(B组)、单次大剂量小檗碱+阿托伐他汀钙组(C组)、多次小剂量小檗碱+单次阿托伐他汀钙组(D组)及多次大剂量小檗碱+单次阿托伐他汀钙组(E组)。给药前后眼眶采血,采用HPLC法测定大鼠体内阿托伐他汀钙的浓度。经DAS 2.0药动学软件处理,获得各组药动学参数。结果大鼠在单次及多次灌胃不同剂量的小檗碱后,阿托伐他汀钙的体内药代动力学参数改变无统计学意义。结论正常用量下小檗碱对大鼠阿托伐他汀钙的药代动力学有一定的影响,但无统计学意义,在人体内的影响仍需进一步研究。     

人尿液三苯双脒代谢物浓度测定及其排泄动力学研究

目的建立人尿液三苯双脒代谢物对-(1-二甲氨基乙亚氨基)苯胺(简称氨脒)浓度测定的HPLC法,并进行其排泄动力学研究。方法16名志愿者随机分为3组,分别空腹口服200、400和600 mg三苯双脒肠溶片,收集服药前及服药后0～2 h,～4 h,～6 h,～8 h,～12 h和～24 h尿液,稀释,以米氮平为内标,乙腈-甲醇-水-三乙胺(35:35:30:0.2,V:V:V:V)为流动相,采用Agilent Extend-C_(18)柱(4.6 mm×250 mm,5μm)分离,检测波长249 nm,流速0.7 mL·min~(-1)。结果氨脒在5～500 mg·L~(-1)浓度范围内线性关系良好,回归方程Y=4.283 X+0.001(r=0.999 4),最低定量限5 mg·L~(-1),低、中、高3个浓度样品相对回收率分别为(99.8±s 2.5)、(99.3±2.2)和(97.0±1.1)%,批内、批间变异RSD均小于5%,-20℃冷冻24 h及7 d稳定,反复冻融稳定。健康志愿者口服低、中、高3个剂量三苯双脒肠溶片后,约有35%～53%的氨脒于服药24 h后经尿液排出,采用DAS 2.0软件计算氨脒t_(1/2)分别为(4.4±1.9)、(4.5±2.3)和(3.8±0.9)h,Ke分别为(0.19±0.10)、(0.19±0.10)和(0.19±0.04)·h~(-1)。结论本方法简单、快速、灵敏、重现性好,能用于健康志愿者口服三苯双脒肠溶片后氨脒尿液浓度的测定,氨脒经肾脏排泄呈现明显的剂量依赖性特征。     

HPLC法快速测定吉米沙星尿药浓度及其尿排泄研究

目的:建立快速测定人尿液中吉米沙星药物浓度的方法,并考察其尿排泄情况。方法:尿样用甲醇处理后以高效液相色谱法测定,色谱柱为Kromasil C18,流动相为乙腈-10 mmol/L醋酸铵缓冲液(pH 2.2,含10 mmol/L高氯酸)(22∶78,V/V),柱温为40℃,流速为1.5 ml/min,检测波长为338 nm。结果:吉米沙星尿药浓度在0.1¹00μg/ml范围内线性关系良好(r=0.999 3),最低检测质量浓度为0.05μg/ml;平均方法回收率为93.0%100μg/ml范围内线性关系良好(r=0.999 3),最低检测质量浓度为0.05μg/ml;平均方法回收率为93.0%¹02.7%,平均提取回收率为103.2%102.7%,平均提取回收率为103.2%¹09.4%,日内RSD为1.3%109.4%,日内RSD为1.3%⁵.7%,日间RSD为5.3%5.7%,日间RSD为5.3%⁹.5%。国产及进口吉米沙星片48 h尿累积排泄率分别为(37.4±7.5)%和(41.2±14.0)%。结论:本方法简便、快速、灵敏、重现性好,适用于吉米沙星尿药浓度测定。     

莫诺苷及其代谢物在大鼠体内的尿排泄动力学

考察莫诺苷及其代谢物在大鼠体内的尿排泄动力学规律.大鼠按20mg/kg灌胃给予莫诺苷水溶液后于不同时间采集尿样,用HPLC法分析尿中莫诺苷及其代谢物的经时变化.尿液排泄药动学试验表明,莫诺苷的尿排泄t_(1/2)为1.69 h,24 h内莫诺苷及其代谢物经尿排泄完全,莫诺苷的排泄量主要集中在0～3 h,约占总排泄量的68.5%,代谢物的排泄量在6～9 h达高峰,约占总排泄量的66.5%.莫诺苷经尿液排泄的总量不足给药量的1.4%.     

小檗碱对葛根素在大鼠体内药动学的影响

目的观察小檗碱对葛根素在大鼠体内药动学的影响。方法建立高效液相色谱（HPLC）法测定大鼠血浆中葛根素的浓度。大鼠灌胃给予葛根素（100 mg·kg^-1）及葛根素和小檗碱混合物（100 mg·kg^-1＋50 mg·kg^-1、100 mg·kg^-1＋100 mg·kg^-1、100 mg·kg^-1＋200 mg·kg^-1）,用HPLC法测定大鼠给药后不同时间血浆葛根素的浓度,DAS ver1.0数据处理软件计算药动学参数。结果葛根素在0.10-10.00 mg·L^-1范围内线性良好（r=0.999 5）。合用小檗碱前后葛根素的主要药动学参数Cmax分别为（0.54±0.05）、（0.59±0.03）、（0.67±0.02）、（0.73±0.03）mg·L^-1;AUC0-∞分别为（4.90±2.91）、（4.63±2.11）、（3.42±2.44）、（6.18±2.57）mg·L^-1·h^-1;CL分别为（26.92±16.24）、（25.94±13.36）、（44.58±30.36）、（18.82±8.47）L·h-1·kg^-1。结论高剂量小檗碱可提高葛根素在大鼠体内的吸收。     

大鼠口服半夏泻心汤及不同配伍组中甘草活性成分的药代动力学研究

目的:建立血浆中甘草苷、甘草素、异甘草苷、异甘草素、甘草酸和甘草次酸的LC-MS/MS分析测定法,研究半夏泻心汤[由半夏和干姜(辛开组),黄连和黄芩(苦降组),人参、大枣和炙甘草(甘补组)组成]及不同配伍组中甘草活性成分在大鼠体内的药代动力学。方法:取血浆样品0.1 mL经甲醇-丙酮-乙酸乙酯(5∶4∶1)沉淀蛋白并萃取后,经Inertsil ODS-SP色谱柱(100 mm×2.1 mm,5μm)分离,流动相为甲醇-0.1%甲酸(含5 mmol.L-1醋酸铵),梯度洗脱。采用电喷雾电离源,多反应监测模式(MRM)测定各成分的血药浓度,DAS 2.0计算药动学参数,SPSS 17.0统计分析。结果:血浆中6个甘草活性成分的提取回收率均大于78%;LC-MS/MS方法测定的日内和日间精密度RSD均小于12%;药动学结果显示,全方配伍后,甘草苷和甘草素的AUC(0-∞)显著高于甘补组和甘补苦降组,相应CL/F显著性降低;异甘草素的Cmax和AUC(0-∞)显著性提高;甘草次酸的Cmax和AUC(0-∞)均高于甘补辛开组和甘补苦降组,Cmax分别高达1.93和4.08倍,AUC(0-∞)分别高达2.49和4.80倍。而甘草酸的AUC(0-∞)在甘补苦降配伍中较高,甘草次酸的AUC(0-∞)则在甘补组中较高。结论:建立的LC-MS/MS分析方法灵敏、准确,可用于半夏泻心汤中活性成分的药代动力学研究。结果表明大鼠口服半夏泻心汤及不同配伍后,各活性成分的药动学参数有一定的变化,全方配伍利于多数活性成分的吸收。     

大黄酸对大鼠灌胃高剂量对乙酰氨基酚的代谢和排泄的影响

目的研究大黄酸对大鼠ig高剂量对乙酰氨基酚代谢、排泄的影响,阐述大黄酸对药物性肝损伤的保护作用及其机制。方法将SD大鼠随机分为对乙酰氨基酚组(2.5 g/kg)和对乙酰氨基酚(2.5 g/kg)联用大黄酸组(125 mg/kg),分别采集两组大鼠血浆、尿液和粪便样品,测定对乙酰氨基酚的体内药物浓度,比较对乙酰氨基酚单用组和联用大黄酸后对乙酰氨基酚的体内药物浓度差异。结果对乙酰氨基酚联合大黄酸后对乙酰氨基酚的药动学行为较单用组有明显改变。与单用比较,联用组对乙酰氨基酚的AUC、C_(max)均有明显降低。尿粪排泄的结果显示对乙酰氨基酚主要以原型、葡萄糖醛酸结合物和硫酸结合物的形式从尿液排泄,48 h内联用组的原型、葡萄糖醛酸结合物和硫酸结合物的尿粪排泄量要高于单用组,表明大黄酸能够促进对乙酰氨基酚的排泄速率。结论大黄酸可以显著影响高剂量对乙酰氨基酚的药动学行为,通过增加对乙酰氨基酚的排泄而降低对乙酰氨基酚在体内的暴露,从药动学的角度阐释大黄酸对药物性肝损伤的保护作用。     

泻心汤黄酮类成分在大鼠体内的药代动力学研究

研究泻心汤中黄酮类成分在大鼠体内药代动力学规律。大鼠灌胃给予泻心汤12 g·kg^-1，给药前及给药后不同时间采集血样或尿样，HPLC法测定黄酮类成分浓度，血药浓度-时间数据和尿药排泄量-时间数据用DAS软件进行动力学分析。采用大鼠肾匀浆温孵法，进行黄芩苷的体外代谢研究。结果显示,黄芩苷、汉黄芩苷血药浓度迅速达峰，药时曲线呈现双峰现象，消除T_1/2均为6 h左右；黄芩苷、汉黄芩苷、黄芩素、汉黄芩素在尿中均有排泄，尿中排泄量占给药量均<10%，尿排泄T_1/2在6～8 h；大鼠肾匀浆可将黄芩苷代谢生成黄芩素，酶动力学参数V_max＝702 nmol·min^-1·g^-1(protein)，K_m＝135 μmol·L^-1。可见，泻心汤中黄酮类成分可迅速吸收进入体内；黄芩苷、汉黄芩苷、黄芩素、汉黄芩素均可从尿排泄，但尿药排泄量较少；肾脏可将黄芩苷代谢成黄芩素。     

R—hap在大鼠体内的组织分布，排泄及药动学研究

测定R-hap在健康Wistar大鼠体内的组织分布，排泄及药动学参数。R-hap采用IODO-GEN标记，测定单次推注给药后^125I-R-hap的组织分布，尿、粪及胆汁的排泄情况。^125I-R-hap药动学参数也是在单次推注给药后测定。R-hap在体内广泛分布，在大部分器官中快速消除。其中肾的含量最高，脂肪的含量最低。累计排泄率为71．81％±2．15％（48小时）及94．71％±1．50％（120小时）。经尿排泄为主要的排泄途径，给药后120小时，尿及粪的累计排泄率分别为80．64％±1．47％，14．07％±0．95％。平均给药时曲线下面积为（8818．4±576．1）Bq／h／mL。R-hap的组织分布，排泄及药动学参数的结果为未来的临床试验设计提供了参考依据。     

荷叶碱在大鼠体内的吸收、分布、代谢和排泄研究

目的荷叶碱为荷叶中的主要活性成分,是一种具有调节血脂和治疗肥胖相关疾病的阿朴啡类生物碱。为了更好地指导临床用药,我们建立了荷叶碱在血浆及各组织匀浆中的定量测定方法,并对其在大鼠体内的吸收、分布、代谢和排泄进行了深入研究。方法大鼠静脉和灌胃给予荷叶碱0.2和10 mg·kg~(-1),在不同时间点收集血浆和组织,以盐酸巴马汀为内标,HPLC-MS法测定给药后荷叶碱在血浆和组织中的浓度。大鼠灌胃给予荷叶碱10 mg·kg~(-1),在不同时间点收集尿液和粪便,经处理后HPLC-MS法测定给药后荷叶碱在尿液和粪便中的浓度。结果空白血浆中荷叶碱在2~2000 ng·mL~(-1)浓度范围内呈良好的线性关系,在血浆中绝对回收率为87.5%,样品在长期储存过程中能保持稳定。荷叶碱的绝对生物利用度较低为(1.9±0.8)%。在体内分布中肾>脾>肝>心>肺>脑。荷叶碱在体内主要以原形存在,尚未发现其代谢产物;荷叶碱主要通过肾排泄(80.7%)。结论本研究建立了便捷而且有效定量测定大鼠血浆中荷叶碱的方法,并对荷叶碱在大鼠体内的吸收、分布、代谢和排泄进行了深入研究,为临床应用该药提供了理论依据。     

Anthraquinone pharmacokinetics in Xiexin decoction and the different combinations of its constituent herbs

Xiexin decoction (XXD), a classical pyretolytic formulation, is composed of Rhei rhizoma (DH) Radix scutellaria (HQ) and Coptis chinensis (HL), and commonly used in the clinical setting. The aim of this study was to investigate the pharmacokinetic differences between the five anthraquinones it contains (aloe-emodin, rhein, emodin, chrysophanol and physcion) in rats after the oral administration of XXD and after the administration of the different combinations of its constituent herbs. Twenty rats were divided into four groups and randomly administered one of the four extracts: DH, DH and HQ (DH-HQ), DH and HL (DH-HL), and XXD (DH-HQ-HL) via intragastric gavage (i.g.). Anthraquinone concentrations in the plasma were determined by an HPLC technique. Pharmacokinetic parameters were calculated from the plasma concentration time data. Compared with DH alone, the DH-HL combination showed maximum plasma concentration decreased (Cmax) and area under curve (AUC) for the values anthraquinones, and a prolonged eliminatun half life (T(1/2)) for rhein, while the DH-HQ combination showed a decrease Cmax for rein and a prolonged T(1/2) for aloe-emodin and physcion. Finally, XXD (DH-HQ-HL) administration resulted in an increased AUC for all five anthraquinones compared to DH-HL, and increased the total of AUC for rhein, emodin, chrysophanol and physcion compared to DH alone. These results showed that the oral bioavailability of the five anthraquinones was significantly decreased by combining DH with HL, whereas HQ increased the amounts of absorbed anthraquinones (except for aloe-emodin), and weakened the effect of HL which inhibited the absorption of anthraquinones.     

Circadian variations in the pharmacokinetics, tissue distribution and urinary excretion of nifedipine after a single oral administration to rats

Circadian variations in the pharmacokinetics, tissue distribution and urinary excretion of nifedipine were examined in fasted rats after administering a single oral dose at three different dosing times (08:00 am, 16:00 pm, 00:00 am). The plasma concentrations, the areas under the plasma concentration-time curve from zero to 6 h (AUC(0-6 h)) and the peak plasma concentration (C(max)) were significantly higher in the rats dosed at 08:00 am (immediately inactive), and was lower at 16:00 pm (most inactive) and 00:00 am (most active). The time to reach the C(max) (T(max)) was the shortest in the rats dosed at 08:00 am. It was very interesting to observe the double peak phenomena in the plasma concentration profiles, showing a larger peak followed by a smaller peak. There was a dosing time dependency on the tissue distribution 30 min after administration, showing a similar tendency to the pharmacokinetic behavior. However, there was no distinct dosing time dependency observed at 2 h after administration due to the extensive disposition. The cumulative urine excretion of nifedipine in the rats dosed at 08:00 am was significantly higher (about two-fold) than in those dosed at 16:00 pm and 00:00 am. The pharmacokinetics of nifedipine in the rats was consistent with that observed in human subjects in terms of the day-night clock time but the biological time was the opposite, as marked by the rest-activity cycles. These results may help to explain the circadian time-dependency of nifedipine pharmacokinetics.     

剂量配伍对泻心汤蒽醌类成分溶出率变化规律研究

目的:研究黄连、黄芩的剂量配伍变化对泻心汤蒽醌类成分在泻心汤中溶出率影响。方法:固定大黄的量不变,应用2因素5水平星点设计法设计泻心汤的剂量比例,用HPLC法测定不同剂量比例泻心汤的蒽醌类成分的含量,计算溶出率,建立数学模型,分析剂量配伍变化对泻心汤蒽醌类成分溶出率变化影响。结果:大黄的量不变,黄连的量与黄芩的量分别不同程度改变时,泻心汤蒽醌类成分的溶出率不同。黄芩的量改变对泻心汤蒽醌类成分的影响较大。得到蒽醌类成分有较好溶出率的剂量比例为大黄-黄连-黄芩=6∶0.17∶5.83。结论:将星点设计-响应面法应用于中药剂量配伍方面的研究,具有方法简便、精度高的优点。非线性回归分析比线性回归分析更适用于复方剂量配伍变化对其有效成分溶出率变化规律的研究。     

Pharmacokinetics and quantitative characterization of cefotiam excretion after intravenous administration to patients after cholecystectomy

Summary Six patients, aged 52 to 71 years, with T-tube drainage of the common bile duct and a urinary catheter after cholecystectomy, were studied in order to evaluate the urinary and biliary excretion and pharmacokinetics of cefotiam in the early postoperative period. Each patient received cefotiam 1 g i.v. as a bolus injection. Cefotiam in plasma, urine, and bile were determined by HPLC. A 2-compartment open model with elimination from the central compartment satisfactorily fitted the plasma levels of the drug. The renal clearance of cefotiam (CL_R=133 ml/min) was an order of magnitude greater than its biliary clearance (CL_B=11.8 ml/min). Glomerular filtration was the main mechanism for elimination of cefotiam. The values of CL_R and CL_B in relation to the total plasma clearance (CL=138. ml/min) demonstrated the negligible role of metabolism in elimination of cefotiam in these patients.This paper was presented in part at the 2nd National Congress of Pharmacology, Plovdiv, Bulgaria, 17–20 May, 1984     

Relations between toxicity and altered tissue distribution and urinary excretion of nicotine,cotinine, and hydroxycotinine after chronic oral administration of nicotine in rats

Tissue distribution and urinary excretion of nicotine, cotinine, and hydroxycotinine after multiple oral administration of nicotine to rats for 4 weeks were studied. Physiological change and serum biochemical parameters were also measured to check dysfunction of organs. Significant change of glutathione S-transferase, aspartate aminotransferase, blood urea nitrogen, and physiological parameters indicated the toxicity in liver and kidney, at the dose of 5 and 10?mg/kg/day. Only the concentration and total amount of cotinine, not nicotine or hydroxycotinine, in the liver and the kidney showed a proportional dose-dependent increase and were highly correlated with toxicity. Saturation of metabolizing enzymes for nicotine was estimated by the change of urinary excreted amount ratio between nicotine and its metabolites. Metabolizing enzyme to produce cotinine from nicotine was saturated after multiple oral dosing for 4 weeks in a low dose (1?mg/kg/day), but within 1 week in the dose of 5 and 10?mg/kg/day.     

泻心汤及其有效成分组合物抗动脉粥样硬化作用的比较研究

目的：在抗动脉粥样硬化（atherosclerosis,AS）主要药理作用环节比较泻心汤（XXD）与有效成分组合物（CECs）的效应,为阐明泻心汤抗AS效应物质基础提供依据。方法：选用转基因Fli1：eGFP品系斑马鱼幼鱼,通过喂食高胆固醇饲料10 d建立AS模型,实验分为空白组、模型组、阳性对照组（辛伐他汀,0.1 μmol·L^-1）、泻心汤组（50,250,500 mg·L^-1）及有效成分组合物组（2.962、14.81、29.62 mg·L^-1）,实验结束后,测定斑马鱼甘油三酯（TG）、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-c）、高密度脂蛋白胆固醇（HDL-c）、丙二醛（MDA）及超氧化物岐化酶（SOD）的含量,观察斑马鱼血管中胆固醇积累的情况。结果：与模型组比较,泻心汤及有效成分组合物能够明显降低斑马鱼TG、TC、LDL-c水平,提高HDL-c水平（P<0.05或P<0.01）;降低MDA水平,提高SOD水平（P<0.05或P<0.01）;抑制血管中胆固醇的积累（P<0.05或P<0.01）,且有效成分组合物的效应强度可达到泻心汤的80%以上。结论：有效成分组合物在调节脂质水平、改善抗氧化能力及抑制血管中胆固醇积累等药理作用环节能较好的代表泻心汤发挥抗AS作用,可认为是泻心汤抗AS的主要效应物质。     

不同剂量染料木黄酮及其代谢产物在大鼠尿中的排泄

目的:研究不同剂量染料木黄酮及其葡萄糖醛酸化代谢产物在大鼠尿中的排泄动力学。方法:将染料木黄酮制成混悬液,按6.25、12.5、50mg.kg-1给大鼠灌胃,于灌胃后不同时间收集尿液,用葡萄糖醛酸酶溶液处理尿液。采用高效液相色谱法测定尿液中染料木黄酮及其葡萄糖醛酸化代谢产物的浓度。结果:6.25、12.5、50 mg.kg-1时,累积以原形经尿液排泄的药物分别为34.79±10.83、187.30±69.96和213.56±30.58μg,累积经尿液排泄的总药物(原形药物+葡萄糖醛酸化药物)分别为217.79±52.06、583.05±106.92和1108.37±88.14μg,累积经尿液排泄的葡萄糖醛酸化代谢产物分别占尿液排泄总量的84.03%、67.88%和80.73%。结论:染料木黄酮在大鼠尿液中主要以葡萄糖醛酸结合形式排泄,原形及其葡萄糖醛酸化代谢产物的排泄呈现明显的非线性剂量依赖性特征。     

Excretion of [3H]triptolide and its metabolites in rats after oral administration

Aim： To investigate the routes of elimination and excretion for triptolide recovered in rats.
Methods： After a single oral administration of [3H]triptolide （0.8 mg/kg, 100 μCi/kg） in Sprague Dawley rats, urine and fecal samples were collected for 168 h. To study biliary excretion, bile samples were collected for 24 h through bile duct cannulation. Radioactivity was measured using a liquid scintillation analyzer, and excretion pathway analysis was performed using an HPLC/on-line radioactivity detector.

Results： The total radioactivity recovered from the urine and feces of rats without bile duct ligation ranged from 86.6%–89.1%. Most of the radioactivity （68.6%–72.0%） was recovered in the feces within 72 h after oral administration, while the radioactivity recovered in the urine and bile was 17.1%–18.0% and 39.0%–39.4%, respectively. The HPLC/on-line radiochromatographic analysis revealed that most of the drug-related radioactivity was in the form of metabolites. In addition, significant gender differences in the quantity of these metabolites were found： monohydroxytriptolide sulfates were the major metabolites detected in the urine, feces, and bile of female rats, while only traces of these metabolites were found in male rats.

Conclusion： Radiolabeled triptolide is mainly secreted in bile and eliminated in feces. The absorbed radioactivity is primarily eliminated in the form of metabolites, and significant gender differences are observed in the quantity of recovered metabolites, which are likely caused by the gender-specific expression of sulfotransferases.     

大鼠一次性灌服酸枣仁汤剂提取物后芒果苷的药代动力学研究

沈阳药科大学 药学院, 辽宁 沈阳 110016