口服丁香酚在大鼠体内药动学研究

目的 建立大鼠血浆中丁香酚含量测定的高效液相色谱法(HPLC)。 方法 丁香酚大鼠灌胃给药后,应用HPLC测定其在大鼠血浆中的含量,色谱柱：Allsphere ODS-2 RP-18(4.6 mm×250 mm,5 μm),流动相：甲醇-0.5%冰醋酸=63∶37 (pH=4.78);检测波长：280 nm;柱温：30 ℃;流速：0.8 mL·min^-1。 结果 丁香酚经口服 14.25 mg·kg^-1的剂量后在体内药动学特征符合二室开放模型。 结论 所建方法简单、灵敏、准确可靠,可用于丁香酚的药动学研究。     

积雪草苷在大鼠体内的药动学研究

目的:研究积雪草苷在大鼠体内的药动学特点。方法:用高效液相色谱法,以葫芦素B为内标,甲醇为血浆蛋白沉淀剂,水-乙腈(24∶76)为流动相,测定一次性给大鼠尾静脉注射积雪草苷(42或126mg·kg-1)后SD大鼠血浆中积雪草苷的浓度。采用3p97程序计算药动学参数。结果:积雪草苷在SD大鼠体内的药动学符合二室开放模型,2个剂量组的t1/2α分别为1.89和1.73min,t1/2β分别为27.08和26.81min,K21分别为0.24和0.20min,K10分别为0.039和0.031min,K12分别为0.11和0.13min,AUC分别为1442.11和5749.78mg·min·L-1,CL分别为0.029和0.022mL·g-1·min-1,MRT分别为39.08和38.70min。结论:积雪草苷在SD大鼠体内的分布消除较快,呈一级动力学特征。     

中枢神经兴奋剂莫达非尼在大鼠体内的药动学

目的:研究SD大鼠单剂量口服莫达非尼后,莫达非尼在大鼠体内的药动学特征.方法:SD大鼠单剂量4.0 mg·kg-1灌胃莫达非尼混悬液,于各时间点,心脏取血,分离血清,用高效液相色谱法测定莫达非尼的浓度,所得血药浓度-时间数据用3P87药动学软件处理,求得药动学参数.结果:莫达非尼药-时曲线符合二室模型,T1/2α为(0.48±0.09) h,T1/2β为(3.55±0.27) h,Tmax为(0.79±0.06) h,Cmax为(3.53±0.05) mg·L-1,AUC0～∞为(14.32±0.30 )mg·h·L-1.结论:莫达非尼在大鼠体内分布较快,消除较慢,具有良好的药代动力学特征.     

萘哌地尔在家犬体内的药动学

目的 建立家犬血浆中萘哌地尔浓度的高效液相色谱分析方法,研究萘哌地尔普通片和缓释片在家犬体内的药动学规律。方法 采用内标法,以Shim-Pack ODS C18柱为固定相,甲醇-乙腈-0.02 mol·L-1磷酸二氢钾(25:25:50)为流动相,维拉帕米为内标,检测波长为240 nm,流速为0.8 mL·min-1,柱温30℃,血药浓度一时间数据采用3P97程序处理并计算药动学参数。结果 血浆中内源性物质对萘哌地尔与维拉帕米均无干扰,萘哌地尔与内标的峰面积之比同萘哌地尔浓度间有良好的线性关系,线性范围为13.6-868 ng·mL-1,最低定量浓度为13.6 ng·mL-1,方法回收率和提取回收率分别为101.2％±7.8％(n=3)、74.6％±3.6％(n=3),日内RSD≤6.9％,日间RSD≤8.4％;家犬口服100 mg萘哌地尔普通片与缓释片后,血药浓度时间曲线符合一室模型,Cmax分别为(635.1±129.8)、(63.7±163.1)ng·mL-1,tmax分别为(1.28±0.57)、(6.67±1.63)h,AUC0-t分别为(3 562±1 265)、(3 297±937)ng·mL-1·h,T1/2(Ke)分别为(3.35±0.68)、(4.01±3.14)h。结论 所建立的血浆中萘哌地尔浓度测定方法灵敏、准确,能较好地满足萘哌地尔药动学研究的需要;萘哌地尔缓释片具有明显的缓释特征。     

静脉注射乌苯美司/5-氟尿嘧啶在大鼠体内的药动学研究

目的:建立大鼠静脉注射乌苯美司/5-氟尿嘧啶(Bes/5-FU)后血药浓度的检测方法,并研究其药动学特征。方法:取6只大鼠股静脉注射Bes/5-FU生理氯化钠溶液84 mg/kg,给药后0.033、0.083、0.167、0.333、0.5、1、2、3、4、6、8、10 h经眼底静脉丛取血,高效液相色谱法分别检测Bes/5-FU和5-FU的血药浓度,用DAS 2.0分析软件计算给药后代谢产物5-FU的药动学参数。色谱柱为Venusil ASB C18,流动相为乙腈-0.05%甲酸(22∶78)(Bes/5-FU)、甲醇-水(5∶95)(5-FU),流速为1 ml/min,检测波长为262.7 nm(Bes/5-FU)、266 nm(5-FU),柱温为25℃,进样量为30μl(Bes/5-FU)、20μl(5-FU)。结果:Bes/5-FU给药后2 h在大鼠体内已基本代谢完全。5-FU药动学参数t1/2为(0.14±0.04)h,MRT0-10 h为(0.17±0.04)h,AUC0-10 h为(17.73±6.27)μg·h/ml,AUC0-∞为(17.78±6.31)μg·h/ml。结论:本方法可快速、准确地检测Bes/5-FU及其代谢产物5-FU在大鼠体内的血药浓度;Bes/5-FU在大鼠体内迅速代谢为5-FU。     

酮咯酸氨丁三醇在大鼠体内药动学

目的:比较研究大鼠尾静脉注射与局部皮肤给予酮咯酸氨丁三醇的药动学行为。方法:采用HPLC法,色谱柱:Dia-monsil C18柱(200mm×4.6mm,5μm);流动相:甲醇-水-三乙胺-冰醋酸(80∶19.9∶0.02∶0.08);流速:1.0mL.min-1;柱温:30℃;检测波长:313nm。结果:酮咯酸氨丁三醇在0.2~100mg.L-1范围内与峰面积呈良好的线性关系(r=0.999 0),日内RSD为2.3%~5.1%,日间RSD为2.2%~12.2%,萃取回收率为86.8%~96.2%,注射剂和凝胶剂的T1/2α分别为(0.4±0.3)h,(2.9±2.6)h;T1/2β分别为(2.7±2.0)h,(9.0±8.5)h。结论:本试验建立的方法操作简单,方法灵敏、特异,结果准确。酮咯酸在大鼠体内药动学行为符合二房室模型;外用给药透皮吸收良好。     

葛根素在大鼠体内的药动学研究

目的研究葛根素在大鼠体内的药动学。方法对大鼠灌胃给药,高效液相色谱（HPLC）法测定葛根素的血药浓度,用DAS2．1．1数据处理软件计算药动学参数。结果葛根素在0．10—10．00mg·L^-1范围内线性良好（r=0．9995）。主要药动学参数如下：t1／2α=（0．549±0．397）h,t1／2β=（9．751±4．585）h,CL/F=（32．937±12．695）L·h^-1·kg^-1,Cmax=（0．545±0．051）mg·L·-1,tmax=（0．799±0．183）h,AUC=（3．384±1．166）mg·L^-1·h^-1。结论建立了HPLC法测定葛根素血药浓度的方法,适用于葛根素的药动学研究,为合理利用葛根素提供参考。     

HPLC法研究SQ0801023在大鼠体内的药动学

目的建立测定大鼠血浆中SQ0801023的高效液相色谱法,并研究其在大鼠体内的药动学特征。方法 Sprague-Dawley大鼠尾静脉注射SQ0801023(30 mg·kg-1)后,于不同时间点采血,HPLC法测定血浆中SQ0801023的浓度,并计算药动学参数。结果大鼠血浆中的SQ0801023在0.2⁵0.0 mg·L-1内线性关系良好(r>0.9991),定量下限为0.2 mg·L-1,提取回收率为75.2%50.0 mg·L-1内线性关系良好(r>0.9991),定量下限为0.2 mg·L-1,提取回收率为75.2%⁸7.2%,日内和日间精密度均小于13.7%。SQ0801023在大鼠体内的主要药动学参数:AUC0-t为(3.66±0.70)mg·h·L-1,AUC0-∞为(3.78±0.70)mg·h·L-1,t1/2为(0.22±0.10)h,ρmax为(17.3±3.90)mg·L-1。结论静注SQ0801023后,SQ0801023在大鼠体内快速代谢和消除。     

褪黑素在Beagle犬体内药动学研究

目的:研究褪黑素在Beagle犬体内药动学参数。方法:6只Beagle犬分别单剂口服褪黑素(3mg/只),以高效液相色谱法测定血中褪黑素浓度,经3p97程序推算药动学参数。结果:褪黑素在体内药-时曲线符合二室模型。t1/2Ka为(0.16±0.10)h,t1/2Ke为(1.21±0.52)h,tmax(0.50±0.18)h,Cmax为(11.27±3.77)ng/ml,CL为(0.13±0.04)L/h,AUC(0～T)为(25.23±7.71)(ng·h)/ml。结论:褪黑素在犬体内口服吸收快、作用迅速,但维持时间短。     

炎琥宁在大鼠体内血药浓度测定方法及其药动学研究

目的:建立以高效液相色谱(HPLC)法测定大鼠血浆中炎琥宁含量的方法,并对其药动学进行研究。方法:色谱柱为VP-ODS C18 Column(150mm×4.6mm,5μm),流动相为甲醇-1%醋酸-三乙胺(65∶35∶0.02),内标物为安定,流速为1.0mL·min-1,检测波长为251nm,温度为40℃。用甲醇沉淀蛋白后取上清液过0.45μm微孔滤膜进样分析,采用DAS1.0软件进行药动学参数估算。结果:炎琥宁进样浓度分别在0.05～1.0μg·mL-1(r=0.9999)和1.0～10.0μg·mL-1(r=0.9998)范围内与各自峰面积积分值之比呈良好线性关系;平均回收率为90.12%,RSD=0.508%(n=3)。大鼠静脉注射4mg·kg-1炎琥宁后,其tmax、Cmax、t1/2α和AUC0～240分别为(5.03±1.2)min、(1.09±7.5)mg·L-1、(0.95±4.4)min和(18.14±1.1)mg·min·L-1。结论:炎琥宁在大鼠体内的药动学过程符合二室模型。     

Preliminary pharmacokinetic studies of Ukrain in rats

Ukrain (thiophosphoric acid derivative of Chelidonium majus L. alkaloids) was administered to rats i.p. at a dose of 28 mg/kg (equivalent to 0.1 LD50). A high performance liquid chromatography (HPLC) method for rapid determination of Ukrain in plasma has been described. It was found that Ukrain rapidly penetrated into the plasma of the rats and the elimination of the drug from the plasma was slower. The results obtained were as follows: absorption rate constant ka = 0.0432 [min-1]; elimination rate constant K = 0.0113 [min-1]; drug half-life t1/2 = 61.32 min; actual concentration of Ukrain in the plasma C = 33 e-0.0113t - 39 e-0.0432t [microgram/ml]; and delay in drug absorption T0 = 5.23 min.     

Very slow chiral inversion of clopidogrel in rats: a pharmacokinetic and mechanistic investigation.

Clopidogrel hydrogen sulfate, a thienopyridine derivative, is an ADP receptor antagonist that inhibits platelet aggregation. Clopidogrel is an enantiopure carboxylic ester of S-configuration. The R-enantiomer is devoid of antithrombotic activity and can provoke convulsions at high doses in animals. During preclinical safety evaluation, the possible chiral inversion of clopidogrel has, therefore, been investigated in vivo after repeated oral administration of different dose levels of clopidogrel to male and female rats. Due to rapid metabolism in the liver and low plasma levels of unchanged drug, possible chiral inversion was assessed by monitoring the plasma concentrations of the carboxylic acid metabolites, i.e., the (S)- and (R)-acid, by means of a stereoselective assay. The production of 4 to 8% of (R)-acid was observed. This could be the result of chiral inversion of either clopidogrel or its main metabolite, the (S)-acid. Thus, the possibility of nonenzymatic and enzymatic inversion of clopidogrel and its carboxylic acid metabolite was studied in vitro by chiral HPLC and (1)H NMR. Nonenzymatic chiral inversion of clopidogrel at 37 degrees C in 0.1 M phosphate buffers could be observed but was found to be slow, with estimated half-lives of 7 to 12 days, depending on the pH. The (S)-acid was configurationally fully stable up to 45 days in phosphate buffers. Neither clopidogrel nor its carboxylic acid metabolites were subject to enzymatic chiral inversion in isolated rat hepatocyte suspensions. We conclude that the nonenzymatic inversion of clopidogrel accounts for the 4 to 8% of chiral inversion seen in vivo in the rat.     

Preliminary pharmacokinetic studies of propylthiouracil in humans

Previous analytical procedures for the analysis of propylthiouracil (PTU) in blood and urine samples are questionable on several points. Therefore, a gas-liquid chromatography method has been developed which is both more sensitive and more specific. Application of this procedure confirmed that the drug was rapidly absorbed and eliminated. The mean terminal half-life in euthyroids was found to be 63 min. One hyperthyroid subject showed a far higher plasma clearance than seen with euthyroids, which requires further study.Supported in part by Grant GM 16496 from the National Institutes of Health.This paper was submitted to a Consulting Editor who served as the Journal Editor during its review process.     

Preliminary investigation of the nasal delivery of liposomal leuprorelin acetate for contraception in rats

The purpose of the study was to investigate the nasal route as a non-invasive alternative for delivery of leuprorelin acetate (leuprolide acetate, LEU) and to achieve an effective concentration of leuprorelin acetate in blood after nasal administration for contraception in rats. The plain drug solution, physical mixture (plain drug along with constituents of liposomes), or drug encapsulated in either neutral or charged liposomes containing 5 microg leuprorelin acetate were administered to rats through the nasal route. The plain drug solution was administered subcutaneously (s.c.). Simultaneous evaluation was performed on the influence of a mucoadhesive agent (chitosan) on nasal absorption of the plain drug and the liposome-encapsulated drug. Blood samples were taken at regular time intervals and subjected to luteinising hormone (LH) analysis using a specific immunoassay kit. The plasma luteinising hormone concentration vs time data of nasal and subcutaneous treatments were plotted and compared with that of subcutaneous administration. Relative percentage of bioavailability (F) for nasal treatments was calculated from plasma concentration vs time plots. Sperm count and fertility performance studies were carried out for selected formulations in rats. Neutral liposomes (LLEU) and negatively-charged liposomes (LLEUn) showed higher relative percentage of bioavailability (F 27.83 and 21.30%, respectively) as compared with the plain drug and the physical mixture (F 10.89 and 10.96%, respectively) after nasal administration. Hence, work on neutral liposomes was continued. F was further improved after incorporation of chitosan i.e. 10.89 to 49.13% for plain leuprorelin acetate and 27.83 to 88.90% for liposomal leuprorelin acetate formulations. Liposomal chitosan formulation administered nasally and leuprorelin acetate solution subcutaneously achieved complete azoospermia. No implantation sites were observed after the mating of female rats with treated males. It was observed that in the treated female rats, the estrous cycles ceased with the same formulations from the first treatment cycle. The findings of these investigations demonstrated that the bioavailability of the nasally-administered liposomal leuprorelin acetate with chitosan formulation was comparable with that of the subcutaneously administered drug. Complete contraception was obtained in male and female rats that had been treated with either the nasally administered liposomal leuprorelin acetate with chitosan or the subcutaneously administered drug.     

莲心碱在大鼠体内的药物动力学研究

用反向HPLC法 ,以己酮可可碱为内标 ,建立了血浆中莲心碱的测定方法 ,血浆标准曲线为A1/A2 =0 3188C - 0 0 6 77,相关系数r =0 9999,回收率及日内、日间精密度均符合要求。根据大鼠颈静脉给药 (8 5 4mg/kg)后测得的血药浓度 ,用 3P87处理后求得的莲心碱的主要药动学参数为 :t1/ 2 (α) =2 5 14min ,t1/ 2 ( β) =49 5 2 2min ,AUC =114 878min·μg/mL ,CL =0 0 743L/ (kg·min) -1,V(c) =0 76 6L/kg。     

A pharmacokinetic study of JOMO-tech in rats.

A pharmacokinetic study of 99mTc labelled JOMO-tech in rats (after intravenous administration of a dose of 20 microg/kg body weight) was conducted. JOMO-tech is a heterogeneous extract derived from Nocardia opaca cell walls. An excellent fitting of the three-compartmental disposition model was achieved. The first apparent elimination half-life was very short (t1/2alpha = 0.0572 +/- 0.01383 h) followed by longer second apparent elimination half-life (t1/2beta = 0.817 +/- 0.1922 h), whereas at late post-treatment time the third apparent elimination half-life (t1/2gamma = 21.7 +/- 2.1 h) proved to be long. The peak concentration in the blood extrapolated to t = 0 yielded 32.3 +/- 7.54 ngeq/ml, this being approximately 2-fold the amount of that measured in the 5th post-treatment minute (16.84 +/- 1.447 ngeq/ml). It was determined that the main route of excretion was renal. Up to the 48th post-treatment hour, 30.03 +/- 2.788% of the dose was excreted via the urine, and only 6.71 +/- 0.973% was excreted in the feces by the 7 rats evaluated. The amount of radioactivity detected in selected tissue samples (expressed in ngeq JOMO-tech/g wet tissue) decreased in the sequence liver > kidneys > lungs > blood > plasma. In the time period studied, the highest amount of the dose was found in the liver, whereas up to the 3rd post-treatment day a practically equivalent part of the dose was found in the excreta and in the liver.     

头孢硫脒在大鼠生理药动学模型研究

目的 建立头孢硫脒在大鼠的生理药代动力学模型.方法 按照血流限速理论,采用Matlab系统构建生理药代动力学模型程序;模型包括血液、心脏、肺、肾脏、肝脏、肠、胃、脾、胰腺、骨骼肌、皮肤、脂肪和甲状腺等生理相关性组织.生理性模型参数归纳自文献,组织-血液平衡分配系数等药物相关系数由实验测定.结果 大鼠经脉给与头孢硫脒200mg/kg后,模型预测的药物浓度与试验观察值符合良好.结论 建立了头孢硫脒在大鼠的生理药代动力学模型.     

Physiological pharmacokinetic modeling of inhaled trichloroethylene in rats

The pharmacokinetics of trichloroethylene (TCE) was characterized during and following inhalation exposures of male Sprague-Dawley rats. The blood and exhaled breath TCE time-course data were used to formulate and assess the accuracy of predictions of a physiologically based pharmacokinetic (PB-PK) model for TCE inhalation. Fifty or 500 ppm of TCE was inhaled by unanesthetized rats of 325-375 g for 2 hr through a miniaturized one-way breathing valve. Repetitive samples of the inhaled and exhaled breath streams, as well as arterial blood, were collected concurrently during and for 3 hr following the exposures and analyzed for TCE by headspace gas chromatography. Respiratory rates and volumes were continuously monitored and used in conjunction with the pharmacokinetic data to delineate uptake and elimination profiles. Levels of TCE in the exhaled breath attained near steady-state soon after the beginning of exposures, and were then directly proportional to the inhaled concentration. Exhaled breath levels of TCE in rats were similar in magnitude to values previously published for TCE inhalation exposures of humans. Levels of TCE in the blood of the 50 ppm-exposed animals also rapidly approached near steady-state, but blood levels in the 500 ppm-exposed animals rose progressively, reaching concentrations 25- to 30-fold higher than in the 50 ppm group during the second hour of exposure. The 10-fold increase in inhaled concentration resulted in an 8.7-fold increase in cumulative uptake, or total absorbed dose. These findings of nonlinearity indicate that metabolic saturation ensued during the 500 ppm exposure. The PB-PK model was characterized as blood flow-limited with TCE eliminated unchanged in the exhaled breath and by saturable liver metabolism. The uptake and elimination profiles were accurately simulated by the PB-PK model for both the 50 and 500 ppm TCE exposure levels. Such a model may be quite useful in risk assessments in predicting internal (i.e., systemically absorbed) doses of TCE and other volatile organics under a variety of exposure scenarios.     

The study of codeine-gluthetimide pharmacokinetic interaction in rats

A high-performance liquid chromatographic (HPLC) assay with native fluorescence detection was developed for the simultaneous quantification of codeine and its two metabolites, morphine and morphine-3-glucuronide (M-3-G), in rat plasma. Solid-phase extraction was used to separate codeine and its metabolites from plasma constituents. Extraction efficiencies of codeine, morphine and M-3-G from rat plasma samples were 97, 92 and 93%, respectively. The chromatographic separation was performed using a reversed-phase C18 column and an elution gradient at ambient temperature. Using native fluorescence detection (excitation at 245 nm and emission at 345 nm), the detection limits of 50 ng/ml for morphine, 25 ng/ml for codeine and 20 ng/ml for M-3-G were obtained. The method had good precision, accuracy and linearity, and was applied to the study of glutethimide's influence on codeine metabolism in rat, following single doses of codeine-glutethimide association. The results confirmed the fact that glutethimide was responsible for a significant increase of morphine plasma levels and for their maintenance in time, concomitant with a significant decrease of M-3-G plasma levels, explained by the inhibition of morphine glucuronidation. In conclusion, glutethimide potentiates and prolongs the analgesic effect of codeine by a pharmacokinetic mechanism.     

Population pharmacokinetic investigation of actinomycin-D in children and young adults

Actinomycin-D is an antineoplastic agent that inhibits RNA synthesis by binding to guanine residues and inhibiting DNA-dependent RNA polymerase. Although actinomycin-D has been used to treat rhabdomyosarcoma and Wilms tumor for more than 40 years, the dose/exposure relationship is not well characterized. The objective of this study was to develop an initial population pharmacokinetic model to describe actinomycin-D disposition in children and young adults from which a prospective study could be designed. A total of 165 actinomycin-D plasma concentration measurements from 33 patients, aged 1.6 to 20.3 years, were used for the analysis. The data were analyzed using nonlinear mixed-effects modeling with the NONMEM software system. Age, weight, and gender were examined as covariates for the ability to explain interindividual variability in actinomycin-D pharmacokinetics. The final model was qualified via predictive check and nonparametric bootstrap procedures. A 3-compartment model with first-order elimination was chosen as the structural model. Allometric expressions incorporating weight were used to describe the effects of body size on actinomycin-D pharmacokinetics. Age and gender had no discernible effects on actinomycin-D pharmacokinetics in the population studied. The predictive check showed that the developed model was able to simulate data in close agreement with the actual study observations. The availability of an initial population pharmacokinetic model to describe actinomycin-D pharmacokinetics will facilitate the development of a large-scale clinical trial to study the actinomycin-D dose/exposure relationship in pediatric patients with rhabdomyosarcoma and Wilms tumor. The covariate analysis described by the current data set suggests that indices of body size captured via allometric expressions improve the partition of variation in actinomycin-D pharmacokinetics from this pilot data set. Relationships between pharmacokinetics and toxicity will be examined in future prospective studies in which children less than 1 year old will be enrolled.