大鼠口服灯盏花素的肠淋巴通道转运研究

建立清醒大鼠肠系膜淋巴管和颈静脉的双插管模型,以探索灯盏花素口服经肠淋巴通道的转运规律。采用HPLC法测定血浆和淋巴液中灯盏乙素浓度。双插管大鼠模型分别进行静注和口服灯盏花素的药动学实验。灯盏乙素静脉注射后存在从血液循环向肠淋巴系统的分布,肠淋巴累积转运量为(2.78±0.25)μg,是静注剂量的0.079 2%。灯盏乙素口服经肠淋巴通道12 h累积转运量为(0.92±0.08)μg,是口服剂量的0.008 3%;口服主要经门静脉通道吸收,绝对生物利用度为4.91%。灯盏乙素与乳糜微粒表面载脂蛋白的结合可能是其肠淋巴转运的主要形式。本研究为通过促进灯盏乙素肠淋巴转运而获得高生物利用度的灯盏花素脂质给药系统的研制提供了生物药剂学基础。     

山茱萸中马钱苷在大鼠体内的药物动力学研究

目的:建立测定大鼠血浆中马钱苷浓度的方法,研究并比较了口服马钱苷单体和山茱萸提取液后马钱苷在大鼠体内的药物动力学过程,考察了马钱苷单体口服后的绝对生物利用度。方法:利用 HPLC 法,色谱柱为反相 C_(18)柱(250 mm×4.6mm,5μm),流动相为甲醇-水(32∶68),流速为1 mL·min~(-1),检测波长236 nm。结果:线性范围15.25～7625 ng·mL~(-1),日内与日间 RSD<15%,回收率93.5%～109.3%。灌胃给药后马钱苷单体消除 t_(1/2)为93.6 min,绝对生物利用度为13.2%;山茱萸提取液中马钱苷消除 t_(1/2)为99.4 min,相对马钱苷单体口服给药的生物利用度为19.4%。结论:马钱苷单体口服生物利用度较低。本文方法灵敏度高,操作方便,适合于马钱苷的药动学研究。     

甘油对川芎嗪在大鼠体内生物利用度的影响

目的考察川芎嗪在不同浓度甘油中的大鼠体内药动学参数和生物利用度。方法采用HPLC检测大鼠灌胃给予川芎嗪甘油溶液和川芎嗪水混悬液后血药浓度的变化。计算其房室模型药动学参数,根据药-时曲线下面积AUC(0～∞)和给药剂量,分别计算其绝对生物利用度。结果川芎嗪血浆样品在0.1919～30.6977μg.mL-1范围内线性关系良好,最低检测限为25.1ng.mL-1,高、中、低三个浓度的提取回收率分别为107%、109%、103%。大鼠灌胃给予20%、40%、60%、80%、100%川芎嗪甘油溶液及川芎嗪水混悬液后,川芎嗪的达峰时间分别为45min、15min、15min、30min、15min、30min,AUC(0～∞)分别为(110.23±15.94)、(101.37±11.79)、(343.72±12.06)、(468.86±63.40)、(411.64±83.11)、(173.03±0.81)μg.min.mL-1,其绝对生物利用度分别为23.02%、21.22%、71.94%、98.12%、86.15%、36.21%。结论 60%、80%、100%的甘油能显著提高川芎嗪的绝对生物利用度。     

姜黄素在大鼠体内药代动力学和生物利用度研究

目的研究姜黄素不同给药途径在大鼠体内的药代动力学和绝对生物利用度。方法建立大鼠血浆中姜黄素的HPLC检测方法。考察大鼠分别经灌胃ig(200 mg·kg-1)、ip腹腔注射(20 mg·kg-1)、舌下静脉iv(10 mg·kg-1)给予姜黄素后血药浓度变化。用DAS2.0软件计算药动学参数,根据腹腔注射、灌胃和静脉给药药-时曲线下面积AUC(0-∞)和给药剂量,计算腹腔注射和口服姜黄素的绝对生物利用度。结果姜黄素浓度在0.05～6.00 mg·L-1范围内线性关系良好(r=0.9998);定量下限为0.05 mg·L-1;低(0.10 mg·L-1)、中(1.00 mg·L-1)、高(4.00 mg·L-1)3个浓度的回收率分别为(99.29±5.40)%、(104.21±4.72)%和(99.83±1.97)%;日内RSD分别为4.49%、3.90%和1.72%,日间RSD分别为4.61%、4.27%和2.00%。大鼠经灌胃、腹腔注射和静脉注射姜黄素后,姜黄素在大鼠体内的代谢过程均符合二室模型,消除半衰期分别为(159.28±18.12)、(90.79±11.55)和(11.96±2.64)min;AUC(0-∞)分别为(86.36±12.90)、(73.39±8.72)、(104.62±11.89)mg.min.L-1。按剂量折算,姜黄素经腹腔注射给药的绝对生物利用度为35.07%,灌胃给药的绝对生物利用度为4.13%。结论姜黄素经不同途径给药在大鼠体内的药代动力学过程相似,腹腔注射给药的绝对生物利用度较高,口服生物利用度低。     

氟比洛芬口服混悬剂的兔药物动力学及其生物利用度

目的:研究氟比洛芬口服给药的药物动力学及生物利用度。方法:利用HPLC法测定氟比洛芬的血药浓度,以交叉给药方式分别给予家兔注射剂和口服混悬剂并且对其药物动力学和生物利用度进行研究。结果:氟比洛芬在家兔体内药动学静脉注射符合二室开放模型,口服符合一室开放模型,氟比洛芬口服混悬剂的绝对生物利用度为61.9%。结论:在进行氟比洛芬剂型研究时应注重提高其口服制剂的生物利用度。     

硝苯地平的生物利用度研究

目的 考察硝苯地平的生物利用度.方法 建立测定大鼠血浆中硝苯地平的HPLC方法测定血药浓度,静脉注射硝苯地平(剂量0.75mg·kg-1)与口服给药硝苯地平(剂量3mg· kg-1)测定血药浓度.结果 经拟舍得出i.v.符合两室模型,i.g.符合一室模型,计算绝对生物利用度为38.02％.结论 结果表明硝苯地平在大鼠体内的绝对生物利用度较低.     

赛西尼在大鼠体内药代动力学和生物利用度研究

目的：研究赛西尼在大鼠体内的药代动力学特性和绝对生物利用度。方法： 大鼠灌胃给药5、10、20、40 mg/kg和静脉注射 5 mg/kg赛西尼后,应用LC/MS/MS分析方法测定各时间的血浆原型药物浓度。采用WinNonlin软件计算药动学参数,t检验法统计实验数据,计算生物利用度。结果： 赛西尼在大鼠体内的药动学过程符合二室模型。在5、10、20、40 mg/kg剂量范围内灌胃给药后,AUC0-T与剂量呈正相关, t1/2分别为（6.26±1.26）、（5.80±4.44）、（7.16±4.40）、（7.38±3.24） h,与剂量非线性相关。比较大鼠灌胃与静脉注射 5 mg/kg赛西尼后的AUC0-T,计算赛西尼的绝对生物利用度为 20.4%。结论：赛西尼的吸收较快,吸收程度中等,在5~40 mg/kg的给药剂量下呈现一级动力学特征。     

芍药苷在大鼠体内的药动学和生物利用度研究

目的建立血浆中芍药苷(paeoniflorin,PF)的HPLC检测方法;研究PF在大鼠灌胃和静注给药的药动学和绝对生物利用度。方法采用阿魏酸作为内标,流动相为乙腈-0.5%甲酸水溶液(30∶70),流速0.8mL·min-1,检测波长芍药苷232nm,内标322nm,色谱柱Diamonsil C18(150mm×4.6mm,5μm)。结果以PF浓度和与内标的峰高比进行回归,回归方程:Y=0.1825 X-0.0256,r2=0.9974,最低检出量为20μg.L-1。PF绝对回收率83.41%～90.74%,日间和日内精密度RSD%均小于5%,PF大鼠灌胃给药的绝对生物利用度为(21.11±7.92)%。结论建立了PF血浆浓度检测方法,此方法可用于测定PF在人或其它动物血浆中的浓度。     

绿原酸大鼠口服吸收绝对生物利用度研究

目的评价绿原酸大鼠口服吸收的绝对生物利用度。方法以绿原酸大鼠静脉注射给药后药动学参数AUC为参照,三组大鼠按照200、400、600mg/kg给药剂量分别灌胃给药,计算相关参数,按公式Fpo(%)=AUCpo×Div/(AUCiv×Dpo)×100%计算绝对生物利用度。结果静脉注射给药后AUC0→t为198.01±42.36mg/L·min.灌胃200、400、600mg/kg三个剂量下的AUC0→t分别为339.39±16.03、1268.31±207.08和2530.35±442.57mg/L·min,绝对生物利用度分别为34.28%、64.06%和85.2%。结论绝对生物利用度的评价为绿原酸制剂开发提供了有益参考。     

穿琥宁肠溶胶囊在犬体内的药物动力学及绝对生物利用度

目的　研究穿琥宁肠溶胶囊在犬体内的药物动力学及绝对生物利用度。方法　家犬 6只 ,随机分为 2组 ,采用单剂量交叉给药方案 ,分别给犬单剂量静脉注射或口服穿琥宁肠溶胶囊 ,用HPLC法测定给药后的血中药物浓度 ,3p97药动学程序处理。结果　穿琥宁肠溶胶囊的药 -时数据符合二室模型 ,Cmax为 2 4 .3μg·ml-1,Tmax为 1.2 6h ,AUC(0→∞ ) 为 2 92 84 μg·ml-1,绝对生物利用度为 30 .0 3%。结论　穿琥宁肠溶胶囊有较好的生物利用度     

Pharmacokinetic behaviors and oral bioavailability of oridonin in rat plasma

AIM: To study the intravenous and oral pharmacokinetic behavior of oridonin and its extent of absolute oral bioavailability in rats. METHODS: Oridonin was administered to rats via iv (5, 10 and 15 mg/kg), po (20, 40 and 80 mg/kg) or ip administration (10 mg/kg). The concentrations of oridonin in rat plasma were determined by a high performance liquid chromatography with electrospray ionization mass spectrometric detection (HPLC/ESI-MS) method and the pharmacokinetic parameters were determined by non-compartmental analysis. RESULTS: The plasma concentration of oridonin after intravenous administration decreased polyexponentially, and the pharmacokinetic parameters of oridonin were dose-independent within the examined range. Oridonin was absorbed rapidly after oral gavage with a t(max) of less than 15 min; the extent of absolute bioavailability of oridonin following oral administration was 4.32%, 4.58% and 10.8%. The extent of absolute bioavailability of oridonin following intraperitoneal administration was 12.6%. CONCLUSION: First order rate pharmacokinetics were observed for oridonin within the range of iv doses, while the extent of absolute oral bioavailability was rather low and dose- dependent. The low and dose-dependent extent of oral bioavailability may be due to the saturation of first-pass effects.     

齐墩果酸磷酸酯二钠盐的药物动力学与生物利用度研究

采用高效液相色谱法对齐墩果酸磷酸酯二钠盐 (disodiumoleanolicacidphosphate,以下简称为OLANa2 )进行了大鼠体内的药物动力学与生物利用度研究。大鼠静脉注射 3种不同剂量 ( 4 0、5 0、6 0mg/kg)的OLANa2 注射液后 ,其药物动力学行为均符合二室开放模型特征 ,且在实验剂量范围内其药时过程为线性动力学。大鼠灌胃及肝门静脉给药后 ,其药时过程符合单室开放一级吸收模型特征。大鼠经灌胃、肝门静脉、颈静脉交叉给药后 ,灌胃的绝对生物利用度为 2 2 0 3% ,肝门静脉注射的绝对生物利用度为 88 89% ,胃肠道代谢或未吸收部分共为 6 6 9%。     

Dose-independent pharmacokinetics of a new neuroprotective agent for ischemia-reperfusion damage,KR-31543, after intravenous and oral administration to rats: hepatic and intestinal first-pass effects

The purpose of this study was to report dose-independent pharmacokinetics of KR-31543, a new neuroprotective agent for ischemia-reperfusion damage, after intravenous (iv) and oral (po) administration and first-pass effects after iv, intraportal, intragastric, and intraduodenal administration in rats. After iv (10, 20, and 50 mg/kg) and oral (10, 20, and 50 mg/kg) administration, the pharmacokinetic parameters of KR-31543 were dose independent. The extent of absolute oral bioavailability (F) was 27.4% at 20 mg/kg. Considering the amount of unabsorbed KR-31543 from the gastrointestinal tract at 24 h (4.11%), the low F value could be due to the hepatic, gastric, and/or intestinal first-pass effects. After iv administration of three doses, the total body clearances were considerably slower than the reported cardiac output in rats, suggesting almost negligible first-pass effect in the heart and lung in rats. The areas under the plasma concentration-time curves from time zero to time infinity (AUCs) were not significantly different between intragastric and intraduodenal administration of KR-31543 (20 mg/kg), suggesting that the gastric first-pass effect of KR-31543 was almost negligible in rats. However, the values were significantly smaller (305 and 318 microg x min/mL) than that after intraportal administration (494 microg x min/mL), indicating a considerable intestinal first-pass effect of KR-31543 in rats; that is, approximately 40% of the oral dose. Approximately 50% of KR-31543 absorbed into the portal vein was eliminated by the liver (hepatic first-pass effect) based on iv and intraportal administration (the value, 50%, was equivalent to approximately 30% of the oral dose). The low F value of KR-31543 after oral administration of 20 mg/kg to rats was mainly due to considerable intestinal (approximately 40%) and hepatic (approximately 30%) first-pass effects.     

Pharmacokinetics and rectal bioavailability of hydrocortisone acetate.

The pharmacokinetics and bioavailability of hydrocortisone after rectal administration of a hydrocortisone acetate foam was determined. Endogenous hydrocortisone was suppressed by dexamethasone administration. Plasma levels were compared with those observed after iv and oral administration. Only a very small part of the rectal dose (100 mg) was absorbed; the mean absolute bioavailability was 2%. There was substantial intersubject variability. Maximum hydrocortisone levels were reached after 2 h and averaged 35 ng/mL. These levels were 10-fold lower than those obtained after oral administration of a fivefold lower dose (20 mg) of hydrocortisone in the same subjects.     

The disposition and metabolism of [14C]piritrexim in dogs after intravenous and oral administration.

The disposition of [14C]piritrexim ([14C]PTX) in male dogs after iv and po doses of 1.8 mg/kg was examined. After either route of administration, greater than 90% of the dose was recovered in the exreta within 72 hr; approximately 20% was recovered in urine and 70% in feces. [14C]PTX was extensively metabolized by dogs; unchanged drug accounted for less than 15% of the dose in the excreta. The O-demethylated metabolites, 2'- and 5'-demethyl PTX, the glucuronide conjugate of 2'-demethyl PTX, and the sulfate conjugate of 5'-demethyl PTX were the major metabolites. Unchanged drug accounted for a large proportion of the drug-related radiocarbon in plasma. The average plasma half-life of PTX after iv administration was 2.6 +/- 0.3 hr, and the average total body clearance was 0.33 +/- 0.13 liter/hr/kg. After po administration, peak plasma concentrations of 0.9 +/- 0.3 micrograms/ml occurred about 1.1 hr after the dose; the absolute oral bioavailability of PTX was 0.63 +/- 0.14. Because the O-demethyl metabolites were active dihydrofolate reductase inhibitors, 2'- and 5'-demethyl PTX were synthesized, and the pharmacokinetics and bioavailability of these compounds in dogs after iv and po administration (5 mg/kg) were examined. The plasma concentration-time data for both compounds after iv doses were described by a two-compartment model, with t1/2 beta = 1.3 and 0.8 hr for the 2'- and 5'- demethyl compounds, respectively. Neither compound showed significant advantages over PTX in terms of pharmacokinetics or bioavailability.     

The pharmacokinetics of 1,2-diethyl-3-hydroxypyridin-4-one (CP94) in rats.

The pharmacokinetics of 1,2-diethyl-3-hydroxypyridin-4-one (CP94) and its 2-(1-hydroxyethyl) metabolite (metabolite A) were examined in male Wistar rats using a chronically cannulated conscious-rat model. Serial blood samples were assayed by a reversed phase HPLC method with UV detection. Following iv doses of 25, 50, and 100 mg/kg, the parent compound was eliminated from blood in a biexponential fashion with an average systemic clearance of 1.5 liters/hr/kg. The mean terminal elimination half-life was 2.02 hr and the mean volume of distribution at steady state was 2.69 liters/kg. The areas under the curve (AUCs) for the 25, 50, and 100 mg/kg iv doses were 15, 36, and 72 micrograms/ml/hr, respectively, suggesting that the disposition of CP94 in rats obeys linear kinetics. The oral bioavailability of CP94 (100 mg/kg) was about 53%. Peak blood concentration occurred at about 0.5 hr after oral administration. Following iv doses of CP94 at 25, 50, and 100 mg/kg, metabolite A peaked at about 0.75 hr.     

The disposition and pharmacokinetics of ketoconazole in the rat

The disposition, biliary excretion, and pharmacokinetics of ketoconazole in Sprague-Dawley rats were determined after intravenous administration. Greater than 80% of the radioactivity after a 5 mg/kg iv dose of 3H-ketoconazole was excreted in the feces. Urinary excretion was essentially complete after 48 hr; however, fecal excretion was prolonged over a 7-day period. Biliary excretion of radioactivity averaged 54.3 +/- 18.0% of the dose over a 7.5-8-hr period in pentobarbital-anesthesized rats. The possibility of enterohepatic recirculation was examined using a linked rat technique. Less than 2% of the radioactivity was found in the recipient bile over 9-12 hr. In eight male rats, the plasma pharmacokinetics of ketoconazole, as determined by an HPLC assay with fluorescence detection, were as follows: VD = 655 +/- 91 ml/kg, Cl = 14.4 +/- 5.1 ml/min/kg, and t 1/2 = 35.0 +/- 12.3 min. Three of the rats were given an additional oral dose to determine absolute bioavailability. The time to peak was 30-60 min, and the bioavailability was 35.8 +/- 3.55%. Previous studies have indicated that ketoconazole is well absorbed in rats; therefore, the poor bioavailability is probably due to first pass metabolism. The prolonged fecal excretion of radioactivity from an intravenous dose was probably caused by slow elimination of ketoconazole metabolites.     

劳拉西泮滴鼻剂兔鼻腔给药的药动学研究

建立了HPLC法测定兔血浆中的劳拉西泮,考察鼻腔和静注给药后家兔体内的药动学特征.结果表明,劳拉西泮在1～75 ng/ml浓度范围内线性关系良好,精密度及回收率试验结果符合生物样品分析要求.家兔静注和滴鼻给予劳拉西泮后,tmax为(9.2±10.2)和(6.7±4.1)min,AUC0(-8)为(3 386.2±520.5)和(1 693.2±818.8) ng-1·min,滴鼻剂的绝对生物利用度可达到62.8％.     

Absolute bioavailability of [14C] genistein in the rat; plasma pharmacokinetics of parent compound, genistein glucuronide and total radioactivity.

The systemic plasma pharmacokinetics of genistein were determined in rats to evaluate the absolute oral bioavailability and make comparison with similar data in the literature derived from humans subjects. The plasma concentrations of genistein, genistein glucuronide and carbon-14 were determined by LC-MS/MS and liquid scintillation counting following oral and intravenous dosing with [14C]genistein (4 mg kg(-1) body weight). The absorption of total radioactivity from the gut, (parent compound and metabolites), was 56 and 111% in male and female rats, respectively. In contrast, the absolute oral bioavailability of genistein in male and female rats was 7 and 15%. There was a significant (P<0.001) difference between Cmax of genistein after intravenous (6921 and 4392 ng/ml) and oral (21 and 22 ng/ml) dosing in male and female rats, respectively. After oral administration, the concentration profile of genistein glucuronide in plasma greatly exceeded that of parent compound during the absorption/distribution phase suggesting extensive first pass metabolism, and provided evidence of entero-hepatic circulation. Selective plasma analysis by LC-MS/MS, without prior enzymatic hydrolysis, enabled ready discrimination between parent and conjugated metabolites and prevented gross overestimation of genistein bioavailability. Pharmacokinetic parameters Cmax, Tmax and AUC were similar to those reported in humans, which supports the use of the rat model for genistein toxicity studies.     

Pharmacokinetics of ketotifen fumarate after intravenous,intranasal, oral and rectal administration in rabbits

The pharmacokinetics of ketotifen fumarate (KF) was examined after administration in rabbits through four different routes (intravenous, intranasal, oral and rectal). The time-course of the plasma concentration of KF after intravenous administration (1 mg/kg dose) fitted a two-compartment open model. KF was rapidly absorbed and showed a high plasma concentration within 0.33 h after intranasal administration. The absolute bioavailability of KF after intranasal administration was 66%. After oral administration at a dose of 1 mg/kg, the plasma concentration of KF was below the detection limit of HPLC analysis. Even at 5 mg/kg, the value of the area under the plasma concentration-time curve (AUC) after oral administration of KF was significantly lower than that after intranasal administration of 1 mg/kg. Oral bioavailability was only 8%. The very low bioavailability of KF after oral administration might be due to the first-pass effect in the liver. We also prepared suppositories containing KF (1 mg/kg) for rectal administration in rabbits. After rectal administration, KF was rapidly absorbed and its bioavailability was 34%. These results indicated that the intranasal route appears the most effective for administering KF, and that rectal administration may be superior to oral administration in terms of bioavailability.