乙烷硒啉与顺铂或氟尿嘧啶联合应用对胃癌BGC-823的治疗作用

目的观察乙烷硒啉与顺铂或氟尿嘧啶联合应用对胃癌BGC-823的体内、外抗肿瘤作用。方法MTT法测定5、10、20、40μmol·L~(-1)乙烷硒啉单药及固定其浓度为5μmol·L~(-1)与顺铂或氟尿嘧啶联合时对BGC-823的生长抑制作用。建立裸鼠移植瘤模型,采用乙烷硒啉、顺铂、氟尿嘧啶单药及乙烷硒啉与后两者联合的不同给药方案,观察抗肿瘤作用。结果乙烷硒啉对BGC-823有明显增殖抑制作用,24、48、72h的IC_(50)值分别是30.23、19.70和11.67μmol·L~(-1),联合后效果明显增强(P<0.05)。体内实验,联合组肿瘤增长率明显降低,与单药组有非常显著差异(P<0.01)。结论乙烷硒啉单药表现明显抗肿瘤作用,与顺铂或氟尿嘧啶联合后可以增效。     

海星甾醇琥珀酸酯(A1998)脂肪乳静脉给药后在大鼠体内的组织分布

目的:研究海星甾醇琥珀酸酯(3β-羟基雄甾-5烯-17酮琥珀酸酯,A1998)脂肪乳经静脉给药后在大鼠体内的组织分布经时变化规律.方法:大鼠单次静脉注射20 mg·kg-1 A1998脂肪乳后,分别于不同时间点剖取各组织脏器,采用HPLC柱前衍生法测定大鼠各组织脏器药物含量.结果:A1998在大鼠体内主要分布于肺、肝、脾等器官,给药后15 min,测得肺脏药物含量最高(32.73±3.87)μg·g-1,脾脏(23.47±8.04)μg·g-1及肝脏(14.87±1.63)μg·g-1次之,均远高于同时间点大鼠血药浓度.A1998在上述3脏器中药物浓度维持时间亦久,至给药36 h后仍能检测出较高浓度,分别为(4.37±2.74),(4.69±2.37)及(8.30±5.96)μg·g-1.静注A1998后心脏及肾脏中药物浓度的经时变化与同时间点血药浓度相似.在胃、小肠、子宫、卵巢、体脂中未检测到药物分布.结论:大鼠单次静脉注射20 mg·kg-1 A1998脂肪乳后,药物在血浆中消除迅速,并快速分布于各组织.A1998在大鼠体内的组织分布具有较强的选择性,各组织中药物浓度经时变化结果提示对肺、肝、脾等脏器具有高度的亲和力.     

紫杉醇脂质体在大鼠和荷瘤裸鼠体内的组织分布

目的：运用LC—MS／MS法测定紫杉醇脂质体在大鼠和荷瘤裸鼠体内的组织分布,比较注射用紫杉醇脂质体和紫杉醇注射液的体内分布特征。方法：大鼠分组后分别iv．7mg·kg-1受试和参比试剂,于给药前、给药后10min、1h、4h采集组织样品;荷瘤裸鼠分组后分别iv．10mg·kg-1受试和参比试剂,于给药前、给药后10min,1h,4h,8h采集组织样品,利用LC—Ms／Ms法对组织样品中药物含量进行测定。结果：大鼠iv．紫杉醇脂质体后10min在肝、心、肾、脑、子宫分布达到最大值．4h后各组织中药物含量均下降：荷瘤裸鼠iv．给药后10min在血、肝、脾、肺、肾、脂肪、睾丸分布量最大,8h后在脾、肠、肝、肿瘤中药物含量依然较高。结论：紫杉醇脂质体和紫杉醇注射液在大鼠和裸鼠体内的组织分布一致。静脉注射紫杉醇脂质体后．均能特异地分布到肝脏、肺和肠等。两制剂比较,紫杉醇脂质体具有更好的靶向性和更高的安全性。     

家兔灌服左氧氟沙星后眼内组织分布及其药动学研究

目的:研究家兔单剂量灌服左氧氟沙星后的眼内组织分布及药动学。方法:27只家兔单剂量灌服左氧氟沙星(24mg·kg-1)后0.125、0.5、1.0、2.0、3.0、4.0、6.0、8.0、12h处死并取眼球各组织制备成匀浆,高效液相色谱法测定眼内各组织中药物浓度,3p97软件计算药动学参数。结果:给药后房水、角膜、虹膜-睫状体、玻璃体和晶体组织中cmax分别为(1.59±0.38)、(8.51±2.72)、(10.58±1.17)、(1.17±0.19)、(1.28±0.39)μg·g-1/μg·mL-1;tmax分别为(0.67±0.24)、(1.00±0.55)、(1.83±0.41)、(0.60±0.34)、(0.75±0.27)h;t1/2β分别为(2.68±0.70)、(3.87±1.24)、(5.73±1.66)、(4.44±1.53)、(4.43±1.78)h;AUC0～12h分别为(4.56±1.32)、(20.90±2.63)、(40.25±3.42)、(4.11±0.60)、(3.28±0.90)μg·h·g-1/μg·h·mL-1。药动学分布呈二室模型。结论:家兔单剂量灌服左氧氟沙星后在眼内各组织中分布较快,且有较高的药物浓度,消除较慢,维持时间较长。     

重组人肿瘤坏死因子相关凋亡诱导配体的药代动力学和组织分布

目的研究重组人肿瘤坏死因子相关凋亡诱导配体(rhTRAIL)的药代动力学和组织分布。方法恒河猴单次静脉滴注rhTRAIL1,5和25mg.kg-1及iv5mg·kg-1后,采用酶联免疫吸附法(ELISA)测定rhTRAIL在恒河猴体内的血药浓度,并采用放射性核素示踪技术结合三氯乙酸(TCA)沉淀和分子排阻高效液相色谱法测定[125I]rhTRAIL在荷瘤裸鼠组织内的含量。结果恒河猴单次静脉滴注rhTRAIL1,5和25mg·kg-1后,各剂量组的药代参数除cmax和AUC以外,均无显著差异,表现出线性动力学性质。恒河猴每天给药1次,连续7d,药物在体内没有蓄积。恒河猴静脉滴注和iv给药对药物的体内清除过程无明显影响。[125I]标记rhTRAIL后的放化纯度大于98%。荷瘤裸鼠iv给予[125I]rhTRAIL后,在各组织广泛分布,总放射性在肿瘤组织中于给药后2h达到高峰,在其他大部分组织中于给药后10min达高峰。给药后10min及2,8和24h,肿瘤/血清的酸沉放射性比值分别为0.07±0.01,0.62±0.17,0.78±0.57和1.66±0.50;给药后24h,肿瘤组织的放射性浓度高于其他组织和血清。结论在研究剂量范围内,rhTRAIL在恒河猴体内表现为线性动力学。[125I]rhTRAIL给药后在荷瘤裸鼠中广泛分布,在肿瘤组织中分布浓度较高,并主要经肾脏排泄。     

微透析技术结合HPLC法比较研究5-氟尿嘧啶在大鼠血液和肿瘤组织中的药动学

目的比较5-氟尿嘧啶在正常大鼠和荷瘤大鼠血液和肿瘤中的药动学差异。方法采用微透析技术结合高效液相色谱-紫外检测器(HPLC-UV),分析静脉注射5-氟尿嘧啶(30 mg·kg-1)后药物在大鼠血液和肿瘤内的药物浓度,经体内回收率校正后,用DAS2.1.1软件拟合药动学参数并加以比较。结果 5-氟尿嘧啶在大鼠血液和肿瘤组织的药-时曲线符合二室模型(W=1/C/C),其消除和分布为一级动力学过程。在正常大鼠和荷瘤大鼠血液中,5-氟尿嘧啶分布无显著性差异。在荷瘤大鼠肿瘤内,药物半衰期为(2.15±0.96)h,消除显著慢于血液(0.51±0.16)h。结论双位点微透析技术可用于活体动物体内同时采集血液和靶组织中5-氟尿嘧啶样品,分析抗肿瘤药物的靶向性,更加客观表现肿瘤内部药物的分布情况,可用于抗肿瘤药物的局部药动学研究。     

多索茶碱在大鼠的组织分布和排泄

目的:研究多索茶碱在大鼠的组织分布和排泄,为临床试验提供依据。方法:采用HPLC紫外检测方法测定大鼠灌胃口服多索茶碱后生物样品中药物的含量。结果:大鼠灌胃口服多索茶碱50mg·kg-1后的组织分布试验表明:药物主要分布在胃、肠组织,其次在肝、肾、脾、脑等组织,大部分组织的药物含量于药后0.5h最高,药后1h除胃组织外其它组织均显著下降,随后一直到2h均缓慢下降;大鼠灌胃口服多索茶碱50mg·kg-1后从(0～12h内)尿、粪和胆汁中排泄的原型药物分别占给药总量的27.12%、1.96%和1.68%。多索茶碱的人血浆蛋白结合率为92.1%。结论:多索茶碱主要分布于胃、肠、肝组织中。从粪和胆汁中排泄的原型药物很少。在尿中发现有3种代谢物。     

埃博霉素B的大鼠体内药动学及组织分布

分别建立了液相色谱-质谱法和高效液相色谱法测定大鼠血浆和组织中的埃博霉素B,并考察该化合物在大鼠体内的药动学及组织分布情况.大鼠按3个剂量(0.5、1和2 mg/kg)静脉给药后测定不同时间点的血浆浓度,数据经拟合处理,符合二室开放模型特征,主要药动学参数如下:t1/28(7.17±0.68)、(7.65±1.40)和(6.68±0.36)h,AUC0(_1) (60.4±6.5)、(160.4±37.8)和(428.8±67.1) ng·ml-1-h.荷瘤Wistar大鼠1 mg/kg静脉给药后,于不同时间点测定各组织药物浓度,结果显示药物迅速从血浆分布到组织,并且在肿瘤中的滞留时间较长.     

特拉唑嗪对左氧氟沙星治疗前列腺炎药动学的影响

目的 探讨盐酸特拉唑嗪联合左氧氟沙星治疗大鼠细菌性前列腺炎时,前者对后者在前列腺组织中药动学的影响.方法 120只细菌性前列腺炎模型大鼠,随机分为实验组与对照组,每组60只.两组动物均静脉注射左氧氟沙星溶液(44mg/kg),其中实验组同时灌服盐酸特拉唑嗪溶液(0.44mg/kg)2次,对照组同时灌服溶媒.分别于给药后1、3、7.5、15、30、60、120、240、480和720min采集动物前列腺组织制作成组织匀浆,HPLC法测定各组织中左氧氟沙星浓度,3p97软件计算药动学参数.结果 实验组与对照组药时曲线均符合二室模型,动力学参数如下:t1/2β分别为(6.57±2.73)和(2.11±0.72)h;tmax 分别为(0.34±1:0.08)和(0.64±0.18)h;Cmax分别为(149.41±41.16)和(72.26±23.26)μg/g;AUC0-12分别为(608.02±226.82)和(253.67±91.68)μg·h/g.两组动物前列腺组织中的左氧氟沙星浓度有显著性差异(P<0.01).结论 盐酸特拉唑嗪能够明显提高左氧氟沙星在前列腺炎组织中的药物分布浓度.     

不同粒径高山红景天超微粉在大鼠体内的吸收

目的:考察不同粒径高山红景天超微粉在大鼠体内的吸收。方法:健康雄性Wistar大鼠18只,随机分为静脉注射红景天苷组(50 mg·kg-1)、灌服高山红景天超微粉1组[平均粒径为(45.96±3.57)μm,8 g·kg-1]和灌服高山红景天超微粉2组[平均粒径为(83.27±0.58)μm,8 g·kg-1],每组各6只。分别于给药前和给药后5、10、15、30、45、60、90、120、180 min股动脉取血0.5 mL,并采用HPLC法测定大鼠血浆中红景天苷浓度。利用Phenix WinNonlin 6.1药动学软件中非房室模型分析方法计算药动学参数,并计算生物利用度。结果:给大鼠灌服高山红景天超微粉2后,在大鼠血浆中未能检测出红景天苷浓度。灌服等剂量高山红景天超微粉1后,在大鼠血浆中能够检测出红景天苷浓度,并且其绝对生物利用度为29.66%。结论:当高山红景天超微粉的粒径小于50μm时才具有细胞破壁效果和良好的吸收。     

Mechanism of S-(1,2-dichlorovinyl)-L-cysteine- and S-(1,2-dichlorovinyl)-L-homocysteine-induced renal mitochondrial toxicity

The mechanism by which the nephrotoxic S-conjugates S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,2-dichlorovinyl)-L-homocysteine (DCVHC) produce toxicity in rat kidney mitochondria was studied by examining their effects on mitochondrial function, structural integrity, and metabolism. Both S-conjugates inhibited succinate-linked state 3 respiration and impaired the ability of mitochondria to retain Ca2+ and to generate a membrane potential; 30-60 min were required for maximal expression of these functional changes. Mitochondrial structure was damaged, as indicated by enhanced polyethylene glycol-induced shrinkage of matrix volume and by leakage of protein and malic dehydrogenase from the matrix; 60-120 min were required for maximal expression of these structural changes. Much shorter incubation times (15-30 min) were required for DCVC and DCVHC to decrease ATP concentrations, to alter the concentrations of several citric acid cycle intermediates, and to inhibit succinate:cytochrome c oxidoreductase and isocitrate dehydrogenase activities. Lipid peroxidation and oxidation of glutathione to glutathione disulfide also occurred. The relative time courses of these pathological changes indicate that the initial effects of DCVC and DCVHC in renal mitochondria are the inhibition of energy metabolism and the oxidation of glutathione. These changes then lead to alterations in mitochondrial function and ultimately to irreversible damage to mitochondrial structure.     

Pyrrolo (1,2-a) quinoxalines (author's transl)

Pyrrolo [1,2-a] quinoxalines 2-Ethoxy-3-acetoacetylquinoxaline (1) reacts with ethylorthoformate/acetic anhydride forming 2-acetyl-1,4-diethoxy-3-hydroxy-pyrrolo [1,2-a] quinoxaline 4a .     

Extra-hepatic GSH-dependent metabolism of 1,2-dibromoethane (DBE) and 1,2-dibromo-3-chloropropane (DBCP) in the rat and mouse

Although DBE is metabolized by both microsomal and cytosolic pathways, it is the latter, GSH-dependent route, that may lead to hepatic and extra-hepatic genotoxicity and mutagenicity. As both DBE and DBCP exhibit predominantly extra-hepatic toxicity, their in vitro GSH-dependent debromination was measured in cytosolic fractions prepared from liver, kidney, testes and stomachs of Sprague-Dawley rats and Swiss-Webster mice. There was a marked species difference between the rat and mouse, with the rat metabolizing DBCP more rapidly than DBE, and the mouse metabolizing DBE more rapidly than DBCP. Hepatic rates exceeded those seen in extra-hepatic tissues in every case. Extra-hepatic rates of debromination represented as much as 84% of the hepatic rates, and generally followed the order: kidney greater than testes greater than stomach. Rates of metabolism for DBE and DBCP represented only a small fraction of the total cytosolic GSH S-transferase activity. These findings suggest significant levels of GSH-dependent metabolism may occur within those tissues associated with the in vivo toxicity of DBE and DBCP.     

Transport and activation of S-(1,2-dichlorovinyl)-L-cysteine and N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine in rat kidney proximal tubules

An important step in understanding the mechanism underlying the tubular specificity of the nephrotoxicity of toxic cysteine conjugates is to identify the rate-limiting steps in their activation. The rate-limiting steps in the activation of toxic cysteine conjugates were characterized using isolated proximal tubules from the rat and 35S-labeled S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (NAC-DCVC) as model compounds. The accumulation by tubules of 35S radiolabel from both DCVC and NAC-DCVC was time and temperature dependent and was mediated by both Na+-dependent and independent processes. Kinetic studies with DCVC in the presence of sodium revealed the presence of two components with apparent Km and Vmax values of (1) 46 microM and 0.21 nmol/mg min and (2) 2080 microM and 7.3 nmol/mg.min. NAC-DVVC uptake was via a single system with apparent Km and Vmax values of 157 microM and 0.65 nmol/mg.min, respectively. Probenecid, an inhibitor of the renal organic anion transport system, inhibited accumulation of radiolabel from NAC-DCVC, but not from DCVC. The covalent binding of 35S label to cellular macromolecules was much greater from [35S]DCVC than from NAC-[35S]DCVC. Analysis of metabolites showed that a substantial amount of the cellular NAC-[35S]DCVC was unmetabolized while [35S]DCVC was rapidly metabolized to bound 35S-labeled material and unidentified products. The data suggest that DCVC is rapidly metabolized following transport, but that activation of NAC-DCVC depends on a slower rate of deacetylation. The results are discussed with regard to the segment specificity of cysteine conjugate toxicity and the role of disposition in vivo in the nephrotoxicity of glutathione conjugates.     

Mechanism of S-(1,2-dichlorovinyl)glutathione-induced nephrotoxicity

S-(1,2-Dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-DL-cysteine are potent nephrotoxins. Agents that inhibit gamma-glutamyl transpeptidase, cysteine conjugate beta-lyase, and renal organic anion transport systems, namely L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125), aminooxyacetic acid, and probenecid, respectively, protected against S-conjugate-induced nephrotoxicity. Furthermore, S-(1,2-dichlorovinyl)-DL-alpha-methylcysteine, which cannot be cleaved by cysteine conjugate beta-lyase, was not nephrotoxic. These results strongly support a role for renal gamma-glutamyl transpeptidase, cysteine conjugate beta-lyase, and organic anion transport systems in S-(1,2-dichlorovinyl)glutathione- and S-(1,2-dichlorovinyl)cysteine-induced nephrotoxicity.