HPLC/MS研究国产盐酸班布特罗片及其代谢物特布他林人体生物等效性

目的研究国产班布特罗片剂和进口片剂进行人体生物等效性研究。方法20名健康受试者随机交叉给药,用液相色谱/质谱联用测定血浆中班布特罗其代谢物特布他林的浓度。结果经数据处理,单次口服国产和进口班布特罗片剂后班布特罗的药代动力学参数:AUC_0-t分别为(52±21)μg·h·L^-1和(51±20)μg·h·L^-1,T_max分别为(2.9±0.9)h和(2.6±0.7)h,C_max分别为(6.0±2.6)μg·L^-1和(6.2±2.9)μg·L^-1。特布他林:AUC_0-t分别为(191±30)μg·h·L^-1和(197±37)μg·h·L^-1,T_max分别为(4.2±1.0)h和(4.2±1.0)h,C_max分别为(10±5)μg·L^-1和(10±4)μg·L^-1。国产班布特罗片剂单次给药后的相对生物利用度为102%±8%(班布特罗),100%±12%(特布他林)。结论经统计学证明两制剂有生物等效性。     

反相HPLC法测定兔血浆异钩藤碱浓度及其药物代谢动力学

用ODS柱分离,甲醇—水(95∶5)为流动相,检测波长UV254nm,建立了兔血浆异钩藤碱浓度的HPLC测定方法。结果显示,血药浓度在0016～16μg·ml^-1范围内呈线性关系,血浆最低检测浓度为0.016μg·ml^-1,绝对回收率为80.5%～85.1%。兔iv IRHY 2及5mg·kg^-1,药代动力学过程符合二室开放模型,T_1/2β分别为1.32h和1.25h。兔经十二指肠给2及5mg·kg^-1后,T_1/2β分别为1.75h和1.26h。生物利用度为42.4%～69.4%。此法简便、快速。IRHY在兔体内吸收迅速,消除也较快。     

十名志愿者口服维拉帕米缓释片药代动力学和心电图研究

对10名男性受试者单剂量po240mgVer缓释片药代动力学及心电图变化进行研究。血药浓度—时间数据用零级吸收过程的一室模型拟合,其药代动力学参数:T_max5.9±1.6h;C_max118.9±37.2μg·L^-1;T₁ 5.4±1.5h;k₀30.5±17.5μg·L^-1·h^-1;T_1/210.8±4.9h。PR间期延长有显著意义,血药浓度与PR间期变化满足S 型模型,其药效学参数:EC₅₀ 64.6±16.9μg·L^-1; E_max54±11ms;s 1.68±0.66。     

双部位吸收模型拟合吉非贝齐在人体中药代动力学数据

测定了8名受试者po吉非贝齐(Gem)600mg后血药浓度一时间数据,观察到血药浓度双峰现象。建立一种双部位吸收药动学模型拟合这些数据,实验值与拟合值吻合好,r²均大于0.99。相应参数如下:T_max1.10±0.46h;T_max32.60±0.73h;C_max113.62±4.3μg·ml^-1);C_max217.22±3.83μg·ml^-1);T₁0.06±0.06h;T₂1.42±0.57h;T₃1.79±0.60h。     

家犬单剂量和多剂量口服阿昔莫司缓释制剂的药代动力学和生物等效性研究

目的研究阿昔莫司缓释片在家犬体内单剂量和多剂量的药代动力学和生物等效性。方法测定6只家犬单剂量和多剂量口服缓释片和普通胶囊后的血药浓度。结果阿昔莫司的药-时曲线符合非隔室模型。单剂量给药后，缓释片和普通胶囊的AUC分别为(158±30)和(147±37) μg·h·mL^-1；T_max分别为(4.3±0.8)和(2.6±1.3) h；C_max分别为(29±6)和(42±10) μg·mL^-1；T_1/2分别为(2.3±0.7)和(1.60±0.10) h；MRT分别为(6.0±0.8)和(3.9±0.7) h；F_r为(108±16)%。多剂量给药后，缓释片和普通胶囊的AUC分别为(209±23)和(195±26) μg·h·mL^-1；T_max分别为(6.3±0.8)和(3.4±1.5) h；C_max分别为(27±4)和(36±5) μg·mL^-1；Cmin分别为(2.2±1.0)和(0.20±0.20) μg·mL^-1；C_av分别为(8.7±1.0)和(8.1±1.1) μg·mL^-1；FI分别为(293±73)%和(448±91)%；F_r为(114±19)%。结论单剂量实验的双单侧检验结果表明：缓释片和普通胶囊生物等效；缓释片具有良好的缓释效果。多剂量实验结果表明：缓释片和普通胶囊生物等效；缓释片的波动系数优于普通胶囊。     

救必应酸在大鼠体内的口服生物利用度研究

摘 要 目的：研究救必应酸在大鼠体内药动学和口服生物利用度。方法: 建立测定大鼠血浆中救必应酸浓度的RP HPLC法。考察大鼠经灌胃和尾静脉给予40 mg·kg^-1的救必应酸后血药浓度变化。采用3p97软件计算分析药动学参数和口服生物利用度。结果: 灌胃组大鼠的C_max为（0.81±0.22）μg·mL^-1,T_max为（45.24±5.13） min,T_1/2为（101.47±8.25） min,AUC为（76.3±13.68）μg·min^-1·mL^-1;静脉注射组的T_1/2为（73.68±11.02） min,AUC为（1 687.4±29.54）μg·min^-1·mL^-1。救必应酸口服利用度为4.52%。结论:救必应酸的口服生物利用度较差。     

高效液相色谱法测定血浆中醋氯芬酸及其在犬体内药代动力学

建立了HPLC法同时测定家犬血浆中的醋氯芬酸及其主要代谢物的浓度。此法简便易行,精密度好,方法回收率91.3%～96.9%,日内、日间RSD为3.69%～8.13%,血药浓度在0.050～51.2μg·mL^-1范围内呈线性关系,相关系数0.9998,当S/N≥3时,最小检测浓度为10ng·mL^-1。此法可同时测定醋氯芬酸及其在体内的主要代谢物。醋氯芬酸po吸收迅速,给药后约12min即达血药浓度峰值,其药—时曲线符合二室模型,T_1/2α仅为2.5min左右,T_1/2β约为137min,代谢物约在110min达到血药浓度峰值,峰浓度为3.20μg·mL^-1,T_1/2β约为140min。     

中毒剂量与治疗剂量克仑特罗在兔体内的药动学研究

目的研究克仑特罗在引起不良反应的大剂量下兔体内的药动学,探讨中毒剂量与治疗剂量的药动学参数存在的差异。方法新西兰兔单剂量灌胃(ig)中毒剂量(150μg·kg^-1)与治疗剂量(5μg·kg^-1)的盐酸克仑特罗溶液,采用酶标免疫分析(ELISA)测定不同时间的血浆药物浓度。两组试验数据采用3P97程序拟合处理,求得不同剂量的药动学参数。结果两组剂量的浓度-时间曲线均符合一室开放模型。中毒剂量与治疗剂量的Ke分别为(0.39±0.08)h^-1和(0.18±0.07)h-1;t_1/2(ke) 分别为(1.82±0.34)h和(4.30±1.61)h;t1/2(ka)分别为(0.67±0.28)h和(1.05±0.28)h;t_(max)分别为(1.48±0.39)h和(2.70±0.22)h;C_max分别为(71.37±37.76)ng·mL^-1和(1.56±0.98)ng·mL^-1;AUC分别为(310.28±115.00)ng·h·mL^-1和(14.28±7.22)ng·h·mL^-1;MRT分别为(3.74±0.51)h和(8.82±2.78)h。结论两组剂量在Ke(P<0.01),t_1/2(ke) (P<0.05),t_1/2(ke) (P<0.05)、t_max(P<0.01),MRT(P<0.01)等存在显著差异;C_max,AUC随剂量增加而增加,C_max/D₀、AUC/D₀无显著性差异(P>0.05),为临床抢救中毒病人提供参考。     

安定在家兔体内的肠胃循环药代动力学分析

6只家兔iv安定5 mg·kg^-1后,浓度—时间数据呈现双峰形。本文提出肠胃循环动力学模型,用于分析实测数据,得到了一般动力学参数:T_1/2(α)=0.21±=0.15 h,T_1/2(β)=2.2+0.6 h,K_e=1.5±0.6 h^-1,K₁₂=2.0±1.0 h^-1,K₂₁=1.0±0.4 h^-1,V₁=3.1±1.6 L·kg^-1,AUC=1.7±0.5μg·h^-1·ml^-1。此外,还求得有关肠胃循环的参数,即:重吸收滞后时间T′=0.25±0.24h,重吸收速率常数K_A=3.5±1.4 h^-1,重吸收率R_A=24±7%。     

高效液相色谱法测定人血清和尿中盐酸青藤碱浓度及药代动力学研究

用RP-HPLC法,以三唑仑为内标,反相C₁₈为分析柱,乙腈—0.01mol·L^-1磷酸二氢钠—四甲基乙二胺(46∶54∶0.22v/v)为流动相,磷酸调至pH6.9,检测波长263nm,测定血清和尿中盐酸青藤碱浓度,线性范围分别为6～480ng·mL^-1和0.06～3μg·mL^-1,平均回收率75.88%和91.35%,日内日间误差小于5%,最低检测浓度血清4ng·mL^-1,尿40ng·mL^-1。8名健康男性志愿者单次口服盐酸青藤碱片80mg,测定血清及尿浓度,该药符合二室开放模型,体内消除符合一级动力学消除过程,主要药代动力学参数:T_1/2α0.791±0.491h,T_1/2β9.397±2.425h,T_{max 1.040±0.274h,Cmax246.604±71.165ng·mL^-1,AUC 2651.158±1039.050ng·h·mL^-1,CL 0.033±0.01ng·mL^-1。}     

Determination of aspirin and salicylic acid in uremic patients' plasma using reversed-phase high-performance liquid chromatography

A simple, rapid, and sensitive method for the determination of aspirin and salicylic acid in plasma of uremic patients is reported. After extraction with hexane, aspirin (ASA) and salicylic acid (SA) were quantified by high-performance liquid chromatography (HPLC) with ultraviolet detection at 229 nm. ASA and SA concentrations and peak-height ratios were linearly related up to 20 micrograms/ml. The lower limit of sensitivity was 0.1 microgram/ml for both compounds. The average recoveries of aspirin and salicylic acid were 27 and 54%, respectively. This procedure offers better performance than do previously described methods. The sample clean-up allows quantitation of a low concentration of aspirin in uremic patients' plasma, commonly rich in interfering endogenous substances.     

Urinary excretion of aspirin.

Six human volunteers were each given single oral doses of aspirin (ASA) ranging from 300-1,500 mg. The unchanged ASA excreted in the urine was proportional to dose and urinary pH. The mean percent (+/- s.d.) of dose excreted was 1.9 +/- 0.67. The clearance for ASA was 1.42 +/- 0.28 1/h. The rate of in vitro hydrolysis of ASA to salicylic acid in urine at 37 degrees C was 4 micrograms/min for an initial ASA concentration of 7.5 mg in 100 ml human urine.     

Studies on the pharmacological bases of fetal toxicity of drugs (VII). Enhancement effect of bacterial pyrogen on the fetal toxicity of salicylic acid

We reported previously that the acute and fetal toxicities of aspirin (ASA) were enhanced by bacterial endotoxin (LPS). In order to clarify the mechanism of the enhancement by LPS, the effects of LPS on the toxicities of salicylic acid (SA), the main metabolite of ASA, were investigated in rats. The following results were obtained: 1) The acute toxicity of SA was significantly potentiated by LPS in male rats. The LD50 of SA with LPS was about one third of that of SA alone. 2) The increase of maternal body weight was inhibited significantly after administration of SA (383 mg/kg, p.o.) with LPS (20 micrograms/kg, i.v.), but not after administration of SA alone. 3) The fetal toxicity of SA including fetal death, resorption, growth retardation and skeletal variations was slightly observed in the dam receiving a single dose of SA on the 15th day of pregnancy, but it was markedly increased by LPS (20 micrograms/kg, i.v.). 4) The half-life period of SA in plasma was increased significantly by the co-administration of LPS in male rats after administration of ASA or SA. All of these phenomena in the rats given SA closely resembled the phenomena previously reported in the rats given ASA. These results suggest that SA might play a main role in the acute and fetal toxicities of ASA, and one of the mechanism of the enhancement effect by LPS on ASA-induced fetal toxicity might be related to the increase of SA concentration in the fetus.     

Pharmacokinetic study of a new oral buffered acetylsalicylic acid (ASA) formulation in comparison with plain ASA in healthy volunteers.

A single-blind, randomized, crossover pharmacokinetic study was carried out to investigate the bioavailability of a new oral buffered 325 mg acetylsalicylic acid (ASA) formulation (ASPIRINA 03) in comparison with a 325 mg plain tablet. Twelve healthy volunteers of both sexes, aged between 20 and 37 years, received buffered or plain ASA on two separate occasions with a wash-out interval of at least two weeks. ASA and salicylic acid (SA) plasma levels were determined by a chromatographic method. The results showed no difference between the area under concentration time curve (AUC0-infinity) ASA values of both formulations (p = 0.19), and buffered ASA relative bioavailability was 102.49% (= bioequivalence). A significant difference was found between the AUC0-30 min ASA values: 90.5 micrograms. min/ml with buffered and 67.7 micrograms. min/ml with the plain tablet (p less than 0.05). The buffered ASA time of maximum concentration was shorter (28 +/- 8 min) than the plain one (38 +/- 19 min, p less than 0.05). The plasma concentrations and pharmacokinetic parameters of SA were not significantly different after the administration of the two ASA formulations. The plain ASA tablet had a significantly lower (p less than 0.05) dissolution rate than buffered ASA tablet. Moreover, the buffered ASA tablet significantly (p less than 0.01) increased the pH by 0.5 units. In conclusion, the bioavailability of the new oral buffered ASA was equivalent to that of plain ASA, but the plasma concentration peak was reached in a shorter time.     

Studies on absorption and metabolism of drugs in febrile animals. (III). Antipyretic effect of acetylsalicyclic acid and aminopyrine and their plasma concentrations in febrile rabbits induced with lipopolysaccharide (author's transl)]

The present investigation was an attempt to clarify the mechanism of combined effect of acetylsalicylic acid (ASA) and aminopyrine (AMI) in febrile rabbits as induced by lipopolysaccharide (LPS). In addition, the possible synergic effect of both agents was studied in relation to the plasma concentration. In febrile rabbits, the plasma concentration of ASA (500 mg/kg, p.o.) was a higher level than in the control, but the concentration of salicylic acid (SA), the metabolite of ASA, was similar to that in the control. The plasma concentration of AMI (100 mg/kg, p.o.) in febrile rabbits was lower than in the control. A dose-dependent antipyretic effect was seen in the successive doses from 125 to 500 mg/kg of ASA, and a similar tendency was also observed in AMI from 25 to 100 mg/kg. To observe the synergic effect of ASA and AMI, we prepared the following three combinations: I (ASA/AMI; 125 plus 75 mg/kg), II (ASA/AMI; 250 plus 50 mg/kg) and III (ASA/AMI; 375 plus 25 mg/kg). Plasma concentrations of ASA, SA and AMI were measured after oral administration of the preparations and these concentrations were lower than in the separate administration of ASA ans AMI. The antipyretic effect of the three preparations was weaker than the expected value, respectively.     

Interactions of saruplase with acetylsalicylic acid, heparin, glyceryl trinitrate, tranexamic acid and aprotinin in a rabbit pulmonary thrombosis model.

In anesthetized rabbits with pulmonary embolized thrombi the interactions of saruplase (recombinant unglycosylated single-chain urokinase-type plasminogen activator, CAS 99149-95-8) with acetylsalicylic acid (ASA), glyceryl trinitrate (nitroglycerin, GTN), heparin, and the antifibrinolytics tranexamic acid and aprotinin have been studied. Lysis rates were evaluated as reduction of the weight and as reduction of the incorporated 125J-fibrin content of the embolized thrombi. In untreated controls the spontaneous 125J-fibrinolysis was 8.3 +/- 0.7% and the thrombus weight was reduced by 55.3 +/- 4.5% (mainly due to loss of H2O) at 195 min after the thromboembolization. Infusion of saruplase (21.5 micrograms/kg.min) for 60 min significantly increased the 125J-fibrinolysis to 36.8 +/- 3.7% and the reduction of the thrombus weight to 69.9 +/- 2.1%. ASA (50 mg/kg p.o.) by itself did not exert a lytic effect; in combination with saruplase ASA insignificantly augmented the 125J-fibrinolysis rate and significantly further increased the thrombus weight reduction. GTN (5.0 micrograms/kg.min i.v.) neither influenced the spontaneous nor the saruplase-mediated lysis rates. Treatment with heparin (200 IU/kg i.v.-bolus plus 50 IU/kg.min i.v.-infusion) resulted in significant greater thrombus weight reduction than observed in untreated controls; in combination with saruplase heparin significantly intensified the lytic effect. Tranexamic acid (30 mg/kg i.v.) and aprotinin (30.10(3) KIU/kg i.v.) completely abrogated the lytic effect of saruplase. Treatment with saruplase alone produced an insignificant decrease of the plasma level of fibrinogen by 23% to 200 +/- 20 mg/dl. ASA, GTN and aprotinin did not influence this slight fibrinogenolysis in saruplase-treated animals. A slight decrease of plasma fibrinogen levels was observed by heparin, whereas the decrease by tranexamic acid was significant.     

Effect of 3-[p-(trans-4-aminomethylcyclohexylcarbonyl)phenyl]propionic acid hydrochloride on gastric mucosal barrier

Effects of 3-[p-(trans-4-aminomethylcyclohexylcarbonyl)phenyl]propionic acid hydrochloride (TEI-5103, TG-51) on mucosal protection, ion permeability, potential difference, glycoprotein content, and bicarbonate secretion as parameters of the mucosal barrier in rats were studied. TEI-5103 (50-400 mg/kg p.o.) prevented the formation of gastric lesions induced by 75% ethanol, 0.6N HCl, and 0.1N HCl + 60% ethanol. Indometacin (10 mg/kg s.c.) given 30 min prior to TEI-5103 dosing slightly attenuated this protective effect. TEI-5103 (20 mg/ml intragastrically) prevented the increase in acid back-diffusion and ion permeability induced by acetylsalicylic acid (ASA, 5 mg/kg intragastrically). It also inhibited the decrease in mucosal potential difference induced by ASA and resultant lesion formation at 1 h after ASA dosing. TEI-5103 (400 mg/kg p.o.) improved the decrease in mucosal high molecular glycoprotein content induced by ASA (100 mg/kg p.o.), whereas it did not change the normal mucosal glycoprotein content. By intra-luminal perfusion of TEI-5103 (10 and 20 mg/ml/min), an increase in CO2 concentration in the perfusate was observed, suggesting heightened bicarbonate secretion. Its effect at 20 mg/ml/min was same as that of prostaglandin E2 (20 micrograms/ml/min). These findings suggest that TEI-5103 has a cytoprotective effect like prostaglandin and promotes the integrity of the mucosal barrier. These effects of TEI-5103 may contribute to its overall anti-ulcer effect.     

Inhibition of arterial PGI2 generation and platelet aggregation by aspirin in rabbits ex vivo

In 63 rabbits the generation of prostacyclin (PGI2) by coeliac and mesenteric arteries and arachidonate-induced platelet aggregation in platelet rich plasma (PRP) were studied at 24th, 48th and 72nd hour after oral administration of single doses of acetyl salicylic acid (ASA) (15, 25 and 50 mg/kg). Only at the lowest dose ASA caused a selective inhibition of platelet cyclo-oxygenase. ASA at this dose had a cumulative inhibitory effect on arterial cyclo-oxygenase when it was administered in an ineffective single daily dose during three days every 24h. It is concluded that in vivo ASA can be hardly considered as a preferential inhibitor of platelet cyclo-oxygenase.     

Acute acetylsalicylic acid poisoning: Treatment with forced alkaline diuresis and diuretics

Summary The effect of acetylsalicylic acid (ASA) in patients with renal insufficiency has been examined. In one investigation (A), in patients with a mean GFR of 23.0 ml/min the acute effects of ASA 750 mg i.v. (lysine-ASA 7.5 ml) and 0.9% NaCl 7.5 ml on renal water and solute output and on the clearance of inulin, creatinine and PAH were compared. In another (B) the effects of simultaneous administration of ASA 750 mg or 0.9% NaCl 7.5 ml i.v. with an infusion of furosemide 250 mg were investigated in six patients (mean GFR 12.9 ml/min) in a cross-over study. In study A there was a significant fall in urinary sodium excretion within the first 15 min after ASA administration, with a maximal decrease to 21% of the control period. Urine flow fell to 35%, osmolal clearance to 41%, inulin clearance to 54% and PAH clearance to 66%, whilst tubular reabsorption of sodium increased. The effect of ASA lasted for 2–6 h. The mean salicylic acid concentration during the first two hours after ASA administration was 60.0 µg/ml, and the mean protein bound salicylic acid (SA) was 70.4%. There was no effect of placebo (0.9% NaCl7.5 ml) on renal function. Pretreatment with ASA 750 mg i.v. attenuated the diuretic effect of furosemide 250 mg, and reduced creatinine clearance significantly within 0–2 h after drug administration.     

Bioavailability studies of etofibrate in rhesus monkeys

Etofibrate (Lipo-Merz) is a newer antilipaemic agent that contains the nicotinic and clofibric acid moieties joined together through a diester link with ethylene glycol. The bioavailability of these moieties in etofibrate was compared to that from equimolar amounts of these drugs administered alone to rhesus monkeys (clofibric acid 354 mg, nicotinic acid 203 mg). For this comparative purpose, analytical methods were chosen which converted etofibrate and its initial metabolites into clofibric and nicotinic acid. Following this treatment, the rate and extent of bioavailability of unchanged nicotinic acid from etofibrate was significantly lower (P less than 0.01) than that from nicotinic acid alone. Mean peak whole blood levels of 11.9 micrograms/ml at 2.8 h and 35.3 micrograms/ml at 1.3 h, respectively, occurred after administration of etofibrate and nicotinic acid alone. The extent of bioavailability of clofibric acid hydrolysed from etofibrate was not significantly different (P greater than 0.05) from that from clofibric acid alone. However, mean peak plasma levels of 127.3 micrograms/ml at 3.6 h and 170.8 micrograms/ml at 2.4 h, respectively, occurred after administration of etofibrate and clofibric acid alone and were significantly different (P less than 0.01). The rates and extent of bioavailability of nicotinic acid or clofibric acid administered as a mixture were similar to that from these drugs administered alone. Thus either drug did not affect the absorption of the other in rhesus monkeys. The half-lives of nicotinic acid (in whole blood) and clofibric acid (in plasma) in rhesus monkeys when these drugs were administered alone were 9.9 h and 1.8 h, respectively.