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。     

替硝唑片在健康人体的药代动力学和相对生物利用度

目的 研究替硝唑片在健康人体的药代动力学和相对生物利用度。方法 采用高效液相色谱法测定20名健康男性志愿者,随机交叉单剂量口服替硝唑片1g后血浆中的药物浓度,计算药代动力学参数和相对生物利用度,并进行生物等效性评价。结果 受试和参比替硝唑片的t_1/2分别为(13.98±1.55)h、(13.80±0.93)h,t_max分别为(2.1±1.0)h、(2.3±0.9)h,c_max分别为(18.60±2.27)mg·L^-1、(18.47±3.14)mg·L^-1,AUC_0-τ分别为(368.49±44.08)mg·L^-1·h^-1、(353.86±40.99)mg·L^-1·h^-1。受试制剂于参比制剂的人体相对生物利用度为104.9±13.4%。结论 两种制剂的药代动力学参数相近,具有生物等效性。     

氯化钾泡腾片人体相对生物利用度研究

目的　探讨内源性药物人体药代动力学及相对生物利用度研究方法。方法　18名健康志愿者按随机三交叉设计进行试验。在研究的3周期中,两周期分别po氯化钾泡腾片或氯化钾普通片剂2g,另一周期不服药作对照,用以排除非药物性钾的影响。每一周期在给药后收集0 - 2 ,2 - 4,4-6 ,6 - 8,8- 10 ,10 - 12 ,12 - 2 4,2 4- 48h尿样,测定尿钾量。用带一级吸收的一室模型拟合尿钾累积排泄量时间数据。以给药后0 - 48h尿钾累积排泄量计算生物利用度,用方差分析和双单侧t检验进行制剂的等效性分析。结果　氯化钾泡腾片的药代动力学参数为T_1/2ke=(6±5 )h ,T_1/2ka=(0.08±0.08)h ,ku=(0.09±0.04)h^-1,X_max/f=(18±8)mmol;氯化钾普通片的药代动力学参数为T_1/2ke=(8±5 )h ,T_1/2ka=(0.11±0.11)h ,k_u=(0.07±0.04)h^-1 ,X_max/f=(18±8)mmol。氯化钾泡腾片相对生物利用度F=97.5 %±15.2%。结论　氯化钾泡腾片和氯化钾普通片剂有生物等效性。     

灯盏花素在家犬体内的药代动力学

目的建立高效液相色谱法测定家犬血浆中灯盏花素主要有效成分灯盏乙素的浓度,研究灯盏花素在家犬体内的药代动力学。方法用高效液相色谱法测定6只家犬iv灯盏花素(以灯盏乙素计为120 mg/只)后不同时间血浆中灯盏乙素的浓度,绘制药-时曲线,计算药代动力学参数。结果灯盏乙素的药-时曲线符合三室模型,其T_1/2 γ,T_1/2α和T_1/2β分别为(1.1±0.8) min,(7.0±2.8) min和(52±29) min;Vc为(880±508) mL;CL为(190±54) mL·min^-1;AUC_0-90和AUC_0-∞分别为(574±134) mg·min·L^-1和(599±132) mg·min·L^-1。结论灯盏花素家犬iv给药后,血浆中灯盏乙素浓度迅速下降,提示制剂开发的剂型选择、临床给药方法或给药间隔时间的确定都应该考虑其T_1/2。     

20(R)-人参皂苷Rg3人体药代动力学研究

目的　研究20(R)-人参皂苷Rg3(GRg3)人体药代动力学。方法高效液相色谱－紫外检测法。结果　8名健康志愿者单剂量口服3.2mg.kg^-1GRg3,其药时曲线符合口服吸收有滞后时间的二房室模型,T_max为(0.66±0.10)h,C_max为(16±6)ng.mL^-1,T_1/2α为(0.46±0.12)h,T_1/2β为(4.9±1.1)h,T_1/2(Ka)为(0.28±0.04)h,AUC_0-∞为(77±26)ng.mL^-1.h;6名健康志愿者单剂量口服0.8mg.kg^-1GRg3,由于血药浓度低,可测数据点少,未进行模型模拟;两组给药剂量与相应C_max实测值比较,二者成正比关系。结论　本品口服吸收快,消除也较快,但血药浓度很低。在所试剂量范围内,GRg3属一级动力学吸收、消除过程。     

注射用灯盏花素脂质体在Beagle犬体内的药代动力学

目的制备灯盏花素脂质体，研究灯盏花素脂质体在Beagle犬体内的药代动力学。方法采用双周期交叉试验法，6只Beagle犬分别单剂量(以灯盏乙素计为28 mg/只)静脉注射自制灯盏花素脂质体和市售普通注射液，用反相高效液相色谱法测定不同时间血浆中灯盏乙素的浓度，采用3P97计算药代动力学参数，并进行统计学分析。结果脂质体和市售注射液的T_1/2α分别为(4.4±0.7) min和(1.8±1.3) min；T_1/2<>分别为(55±27) min和(28±23) min；V_c分别为(1 580±265) mL和(2 460±2 200) mL；CL_s分别为(88±10) mL·min^-1和(324±69) mL·min^-1； AUC_0-720分别为(363±42) μg·min·mL^-1和(102±19) μg·min·mL^-1。两种制剂的T_1/2α，CL_s及AUC_0-720经方差分析后均存在极显著或显著性差异。结论与市售普通注射液相比，灯盏花素脂质体Beagle犬静脉注射给药后，大大提高了血药浓度，显著改善了灯盏乙素原药的药代动力学性质，具有缓释作用。     

尿中丹参素的测定及其在人体的药代动力学

目的：分析丹参素在人体内的药代动力学及其测定方法。方法采用尿药法研究丹参素的测定及其在人体的药代动力学。本文选取C18小柱对尿样中的丹参素进行净化和富集,然后再采用ODS柱上以乙腈－0．01mol? L －1磷酸二氢钾溶液（pH为2．8）为流动相,再进行280nm检测。结果健康人体po含丹参素20mg的复方中药颗粒剂B和丹参水煎剂后,丹参素的消除半衰期分别为（0．93±0．16）h、（0．94±0．24）h,8h内体积丹参素尿药累计排泄率分别为（6．21±2．79）％、（14．01±4．02）％。结论正常剂量下的丹参素可以由胃肠道直接吸收,并且可以经过原型从肾脏排泄。但是服用复方制剂后,丹参素的尿药累计排泄率与单用丹参煎剂对比显著降低,但两者的消除半衰期差异无统计学意义（P＞0．05）。     

LC-MS/MS法测定人血浆中辛伐他汀的浓度及相对生物利用度

目的 建立人体血浆中辛伐他汀的LC-MS/MS测定方法,研究辛伐他汀片在男性健康志愿者体内的药代动力学行为,评价其生物利用度和生物等效性。方法 20名健康成年男性志愿者采用随机分组自身交叉对照试验设计,单剂量口服辛伐他汀片40 mg后,用LC-MS/MS联用法测定血浆中药物浓度。结果 试验制剂和参比制剂的主要药代动力学参数:t_max分别为(1.8±1.3)h和(2.10±1.00)h;c_max分别为(7.12±1.61)μg·L^-1和(7.38±1.54)μg·L^-1;AUC_(0-24)分别为(30.50±11.25)μg·L^-1·h^-1和(30.17±10.21)μg·L^-1·h^-1;t_1/2分别为(3.90±0.78)h和(3.76±0.85)h。以AUC_(0-24)计算的试验制剂的相对生物利用度为101.2%±7.8%。结论 建立的分析方法准确灵敏,测得的数据可靠,统计学分析表明两种制剂生物等效。     

HPLC-MS/MS法测定人体色甘酸钠血浆浓度及其药代动力学研究

采用HPLC-MS/MS法测定人血浆中色甘酸钠浓度，进行其滴鼻液和鼻用喷雾剂的药代动力学研究并评价其生物等效性。采用高效液相分离系统，流动相为乙酸铵-甲醇(含50%乙腈)(15∶85)，固定相为AGT Venusil XBP C₁₈(250 mm×4.6 mm ID， 5 μm)色谱柱。采用质谱检测系统， ESI离子源， 正离子模式， 多级反应监测(MRM)方式， m/z 469→263.1(色甘酸钠)， m/z 447.2→327.1(内标，普伐他汀钠)。在0.3～20 ng·mL^-1色甘酸钠血药浓度呈线性关系， 定量限为0.3 ng·mL^-1， 回收率在94.1%以上， 日内日间的RSD均小于14.3%。单剂量给药色甘酸钠鼻用喷雾剂或滴鼻液， 其药代动力学参数T_1/2分别为(1.82±0.54)和(1.59±0.52) h； T_max分别为(0.47±0.12)和(0.44±0.15) h； C_max分别为(9.79±4.66)和(10.88±4.05) ng·mL^-1， AUC_{0-5 h}分别为(11.52±3.46)和(12.63±4.23) ng·mL^-1·h。色甘酸钠鼻用喷雾剂相对生物利用度F_r为(93.6±13.8)%。本法灵敏度高， 适用于色甘酸钠治疗药物监测及其药代动力学和生物利用度研究。     

人血浆中O-去甲右美沙芬的测定及药代动力学研究

目的建立直接测定人血浆中O-去甲右美沙芬的方法,并应用于药代动力学研究。方法18名健康受试者单剂量po氢溴酸右美沙芬60 mg后,血浆样品经液-液萃取,通过液相色谱-质谱-质谱联用法测定其活性代谢物O-去甲右美沙芬的浓度,用非室模型计算药代动力学参数。结果O-去甲右美沙芬测定的线性范围为0.2～80 μg·L^-1;其主要药代动力学参数T_max为(2.1±0.7) h,C_max为(14±8) μg·L^-1,T_1/2为(3.8±1.8) h,用梯形法计算,AUC_0-t为(60±37) μg·h·L^-1。结论该法灵敏度高,操作简便,可直接测定活性代谢物,适用于右美沙芬的临床药代动力学研究及制剂的生物等效性评价。     

Pharmacokinetics of a new beta-adrenoceptor blocking agent, LF 17-895, in man.

The pharmacokinetics of a new potent beta-adrenoceptor blocking drug, bis-4-(2-hydroxy-3-isopropylamino-propoxy)-2-methyl indole sulphate (LF 17-895), have been studied in 5 volunteers after single oral (10 mg) and intravenous (4 mg) doses in a cross-over design. Following oral administration adsorption was rapid with peak plasma concentrations recorded after 3 h. Following the intravenous dose a biphasic decline of the plasma level curve was observed. The half-life of plasma elimination during beta-phase was 4.6 +/- 0.7 (p.o.) and 4.7 +/- 0.3 (i.v.) h, respectively. Absorption of the drug was 88.3 +/- 9.6% comparing the areas under the curve. 28.4 +/- 2.2% of the dose given i.v. was excreted in urine unchanged. When the pharmacokinetic data obtained with LF 17-895 were compared with those of pindolol, which differs only in lacking one methyl group in position 2 at the indole ring, only minor differences were seen: absorption of pindolol as well as plasma elimination were slightly faster.     

Pharmacokinetics of digoxin and main metabolites/derivatives in healthy humans

Three healthy, young male volunteers received doses of 0.6 and 1.2 mg of specifically labelled [3H]digoxin each by intravenous (i.v.) bolus injection and oral (p.o.) administration in accordance with a randomized four-way crossover design. Plasma, urine, and feces samples were taken over an interval of 144 h after drug administration. Total radioactivity and individual radioactivity assignable to digoxin and its metabolites were measured. After i.v. administration, the mean +/- SD recovery of total radioactivity, as percent of dose, was complete, urine 81.3 +/- 2.0% and feces 17.1 +/- 2.8%. The mean recovery of digoxin and that of its metabolites in urine was digoxin 75.6 +/- 3.0%, dihydrodigoxin 2.8 +/- 1.6%, digoxigenin bisdigitoxoside 1.6 +/- 0.1%, and additional metabolites 1.5 +/- 0.3%. Judging from the metabolite data in urine and considering the 5% impurity of the administered dose, metabolism of digoxin appeared to be insignificant after i.v. administration. The total and renal clearances of digoxin were, on average, 193 +/- 25 ml min-1 and 152 +/- 24 ml min-1. The mean steady state volume of distribution was 489 +/- 73 L and the mean residence time 41 +/- 5 h. For the metabolites dihydrodigoxin and digoxigenin bisdigitoxoside the mean residence times were on average 35 +/- 9 h and 53 +/- 11 h; the renal clearances were 79 +/- 13 ml min-1 and 100 +/- 26 ml min-1. After p.o. administration, the mean recovery of total radioactivity, as percent of the dose, was also complete, urine 65.7 +/- 1.98% and feces 31.6 +/- 7.6%. The mean recovery of digoxin and that of its metabolites, as percent of dose, in urine was digoxin 51.5 +/- 11.4%, dihydrodigoxin 4.5 +/- 3.9%, digoxigenin bisdigitoxoside 1.9 +/- 0.1%, polar metabolites 5.5 +/- 3.8%, and additional metabolites 1.3 +/- 0.6%. After p.o., as compared to i.v. administration, larger amounts of all the metabolites were formed in accordance with first pass metabolism/degradation. Maximum mean plasma concentrations of 4.3 +/- 2.5 ng ml-1 and 9.5 +/- 1.1 ng ml-1 for digoxin were observed at 40 +/- 10 min after p.o. administration of 0.6 and 1.2 mg of the drug. The mean absolute bioavailability of digoxin from an aqueous solution was 0.67 +/- 0.14. Renal clearance and mean oral residence time for digoxin were on average 176 +/- 28 ml min-1 and 37 +/- 4 h after p.o. administration.(ABSTRACT TRUNCATED AT 400 WORDS)     

哌拉西林对健康男性志愿者依替米星药动学的影响

目的:探讨哌拉西林(piperacilin,PIP)对依替米星(etimicin,ETI)健康男性志愿者健康药动学的影响.方法:采用自身交叉试验,单用组:ETI 200 mg,静脉滴注;合用组:静脉推注PIP 2 g后,继之给予ETI200 mg,静脉滴注.血、尿中ETI浓度测定采用微生物法,检测菌为短小芽胞杆菌.结果:单用组和合用组的药时曲线均符合二房室开放模型,主要药动学参数如T1/2β、AUC分别为(1.9±0.4)和(1.9±0.2)h;(38±7)和(41±8)mg·h·L~(-1);12h尿药回收率分别为(56±8)％和(56±6)％.经统计学处理均无显著性差异(P>0.05).结论:两药合用时PIP对ETI健康男性志愿者药动学无明显影响.为临床两种药物合用提供了药代动力学依据.     

清胰煎剂与颗粒中4种成分在大鼠体内的药动学比较

目的比较清胰煎剂与颗粒中主要有效成分药动学参数的一致性。方法两组大鼠分别灌胃给予同等生药量的清胰煎剂和颗粒后,采用液相色谱-串联质谱联用(LC-MS/MS)法同时测定不同时间点血浆中芦荟大黄素、大黄素、大黄酸、大黄酚的血药浓度,采用Pk Solver软件计算相关药动学参数。结果清胰煎剂组有效成分芦荟大黄素、大黄素、大黄酸、大黄酚的达峰时间(tmax)分别为0.72,0.45,0.60,0.20 h;血浆消除半衰期(t1/2)分别为9.36,9.68,5.18,5.47 h;峰浓度(Cmax)分别为107.27,14.92,1363.6,96.02 ng·m L-1;血药浓度-时间曲线下面积(AUC0-∞)分别为496.31,105.60,3831.79,481.75 ng·h·m L-1。清胰颗粒组有效成分芦荟大黄素、大黄素、大黄酸、大黄酚的tmax分别为0.08,0.18,0.18,0.47 h;t1/2分别为5.61,6.96,4.66,6.51 h;Cmax分别为96.83,11.46,1249.27,96.68 ng·m L-1;AUC0-∞分别为369.68,70.59,5536.66,435.77 ng·h·m L-1。清胰颗粒组4种成分主要药动学参数(tmax、t1/2、Cmax、AUC0-∞)与煎剂组比较均差异无统计学意义(均P>0.05)。结论清胰煎剂和颗粒具有相似的药动学特征。4种成分均吸收迅速,可为清胰制剂的临床应用提供参考。     

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     

Pharmacokinetics of cisplatin and relation to nephrotoxicity in paediatric patients

BACKGROUND: Cisplatin is a highly effective and frequently used drug in the chemotherapy of solid tumours in children, but only limited data are available on the pharmacokinetics of cisplatin and its associated nephrotoxicity in paediatric patients. METHODS: We investigated the pharmacokinetics of free platinum (Pt) in 12 children (25 courses) receiving cisplatin (75-120 mg/m2) either as a continuous 72-h infusion, prolonged single 6-h infusion or repetitive 1-h infusions. Plasma and urinary Pt concentrations were analysed using atomic absorption spectroscopy. Cisplatin-induced nephrotoxicity was determined using creatinine clearance and several glomerular and tubular marker proteins. RESULTS: Using a two-compartment model the pharmacokinetic parameters for free Pt were: initial half-life 21.6 +/- 9.6 min, terminal half-life 25.9 +/- 16.2 h, area under the plasma concentration-time curve (AUC) 13.5 +/- 4.97 (microg/ml) x h/(100 mg/m2) and cumulative renal elimination(infinity) 41.7 +/- 6.6% of dose. Higher cisplatin delivery rates led to higher peak concentrations of free Pt in plasma and urine and to lower cumulative renal Pt elimination (P < 0.01). During all courses, increases of urinary albumin and alpha1-microglobulin excretion were documented. The creatinine clearance decreased significantly to 70% of baseline values. Correlations were found between both peak free Pt concentrations in plasma and in urine and the maximum of urinary excretions of albumin and of N-acetyl-beta-D-glucosaminidase and the nadir of the glomerular filtration rate (P < 0.05). CONCLUSIONS: With respect to nephrotoxicity, long-term infusions of cisplatin seem to be preferable over intermittent bolus administration in paediatric patients. The best predictive pharmacokinetic parameters for cisplatin-associated nephrotoxicity in children are peak free Pt concentrations in plasma and urine.     

Pharmacokinetics of pyrazinamide in plasma and CSF of rabbits following intravenous and oral administration

The pharmacokinetics of pyrazinamide (PZA) in cerebrospinal fluid (CSF) and plasma of 10 rabbits were studied after separate intravenous (i.v.) and oral (p.o.) administration, in a cross-over study. Concentrations of PZA in biological fluids were determined by high performance liquid chromatography (HPLC). After p.o. dose PZA was absorbed rapidly and peak plasma concentration was attained at 0.5 h post administration. After i.v. dose, the plasma PZA concentrations declined rapidly within 10 min and subsequently more slowly following a bi-exponential manner. No difference was observed in the area under plasma concentration-time curves indicating oral absorption was complete and no apparent first-pass metabolism occurred. The (mean +/- S.D.) elimination t1/2 after i.v. (1.04 +/- 0.18 h) was significantly shorter (P less than 0.0005) than that after oral (1.95 +/- 0.63 h) dose and the apparent volume of distribution was also significantly smaller (P less than 0.005) after i.v. (3.211 +/- 0.412 l) than after oral (5.936 +/- 1.607 l) administration. The elimination t1/2 of PZA in CSF was nearly identical to that in plasma after either i.v. (1.07 +/- 0.20 h) or p.o. (1.84 +/- 0.56 h) administration. There is no apparent barrier in rabbits for the penetration of PZA into CSF from the general circulation.     

The effect of enzyme inhibitor and absorption site following [D-ala2, D-leu5]enkephalin oral administration in rats

The effects of enzyme inhibitor, amastatin, and absorption site following intravenous (i.v.) oral (p.o.), jejunal and ileal administration of [D-ala(2), D-leu(5)]enkephalin (YdAGFdL) were investigated in rats. Model dependent and independent pharmacokinetic parameters were obtained and compared. Linear pharmacokinetics of YdAGFdL were evaluated at 0.28 and 500 microg doses for i.v. and at 1, 500, and 1000 microg for p.o. and ileal routes. Plasma samples were collected and assayed for intact YdAGFdL using a radiometric thin layer chromatography. The clearance (CL) and half lives of the distribution and elimination phases following the 0.28 microg (n=6) i.v. dose were 42.7+/-26.2 (S.D.) ml/min, 0.48+/-0.17 min, and 3.98+/-0.92 min, while those of the 500 microg dose (n=6) were 48.0+/-23.3 ml/min, 0.59+/-0.25, and 6.81+/-3.12 min, respectively, suggesting apparent linear kinetics. The CL values were close to the cardiac output of rats (50 ml/min) indicating very rapid elimination from the body. Mean bioavailability (F) values following p.o. (n=15), jejunal (n=4), and ileal (n=16) administration were 0.40+/-0.24% (S.E.), 1.25+/-0.39, and 1.78+/-0.40, respectively, and were not significantly different (p<0.05) among three doses (1, 1000, 5000 microg). The F value of YdAGFdL following ileal administration in the presence of amastatin was 8.76+/-4.47% (n=6), a 22 fold increase over po administration and a five fold increase over ileal administration without an inhibitor. These results indicate that 'effective' oral delivery of small peptides may be achievable.     

Pharmacokinetics of vinpocetine in humans

The pharmacokinetics of ethyl-apovincaminate (vinpocetine, Cavinton), a new vincamine derivative has been studied in volunteers after p.o. and i.v. administration. The concentration of the drug was determined by mass-fragmentography in human plasma. There was a biphasic elimination of the substance after i.v. injection with a T1/2 alpha of 0.136 h and with a T1/2 beta of 4.83 h. The value of Vdss (2.1 l/kg) shows a high adsorption of the drug by tissue proteins. The clearance rate of elimination was 0.366 l/h/kg. Oral administration of the drug resulted in maximum plasma concentration 1--1.5 h after the administration with values of 20--62 ng/ml. The bioavailability of the drug--calculated from the ratio of the areas under the concentration-time curves--proved to be 56.6 +/- 8.9%. Unchanged vinpocetine could not be detected in urine. From the results two-compartment open models were constructed and the steady state concentrations after multiple dosing were computed.     

Pharmacokinetics of ranitidine in patients with renal failure

The pharmacokinetics of ranitidine were studied in ten patients with renal failure (creatinine clearance, 6-54 mL/min) after intravenous (IV) (50 mg) and oral doses (150 mg). After oral administration, peak plasma concentrations of 378-808 ng/mL were obtained in two to six hours. Plasma concentrations declined very slowly and concentrations greater than 100 ng/mL were obtained for 16 to 20 hours after the dose. The elimination half-life following oral administration was 8.5 +/- 2.8 hours (standard deviation [SD]), and the bioavailability of ranitidine was 43.3% +/- 10.5%. After IV administration, the elimination half-life, plasma clearance, renal clearance, and volume of distribution were 7.0 +/- 1.0 hours, 170 +/- 38 mL/min, 36.0 +/- 25.0 mL/min, and 1.3 +/- 0.4 L/kg, respectively. About 20% of the IV dose and 9% of the oral dose were recovered unchanged in urine. There was a significant correlation between the renal clearance of ranitidine and creatinine clearance (r = .74, P less than .05) after IV administration. The elimination half-life in patients with renal insufficiency is about three times greater than that reported in the literature for healthy subjects. Similarly, the plasma clearance in these patients is about 20% of that reported in healthy subjects. The results indicate that ranitidine elimination is appreciably reduced in renal failure and that an adjustment of dose in patients with renal failure is warranted. A dose of 75 mg bid may be adequate in maintaining the therapeutic plasma concentrations that are required for adequate H2-blocking activity.