CYP2D6抑制剂对艾瑞昔布大鼠体内药代动力学的影响

目的考察CYP2D6抑制剂帕罗西汀对艾瑞昔布在大鼠体内药代动力学的影响。方法选用甲苯磺丁脲为内标,色谱柱为Diamonsil C18柱(150 mm×4.6 mm,5μm),流动相为甲醇-水-甲酸(85∶15∶0.1,V/V/V),等度洗脱,流速为1.0 mL/min,柱温为30℃。将40只健康雄性SD大鼠随机分为实验组和对照组,各20只,实验组大鼠灌胃帕罗西汀溶液2 mg/kg,对照组大鼠灌胃等量1‰羧甲基纤维素溶液,1次/日,连续给予7 d。两组大鼠均于第8天灌胃艾瑞昔布灌胃液(20 mg/kg),并按时取血,测定血药浓度,采用DAS 2.1.1软件拟合药-时曲线(AUC),并计算药代动力学参数,采用SPSS 13.0统计学软件分析。结果实验组的0-∞药时曲线下面积(AUC0-∞)为(1730.4±606.5)mg/(h·L)明显高于对照组的(1331.3±592.6)mg/(h·L)(P<0.05);实验组的峰浓度(Cmax)为(192.1±70.8)mg/L,明显高于对照组的(162.2±53.0)mg/L(P<0.05);实验组的清除率(CL)为(0.01±0.01)L/(kg·h),明显优于对照组的(0.02±0.01)L/(kg·h)(P<0.05)。结论CYP2D6抑制剂帕罗西汀预处理的大鼠,其体内艾瑞昔布的暴露量增大,清除率减小。CYP2D6抑制剂减慢了艾瑞昔布在大鼠体内的代谢,推断CYP2D6参与了艾瑞昔布的代谢。     

酮康唑对奥拉西坦在大鼠体内药代动力学的影响

目的建立测定大鼠血浆中奥拉西坦含量的高效液相色谱法,研究酮康唑对奥拉西坦在大鼠体内药代动力学的影响。方法色谱柱为DiamonsilRPC18柱(250mm×4.6mm,5μm),流动相为乙腈-水(3.2:96.8),流速为0.8mL/min,检测波长210nm,柱温40℃,进样量20μL。试验组大鼠连续灌胃给予酮康唑(50mg/kg,每日1次)7d后,单次灌胃给予奥拉西坦(200mg/kg),测定奥拉西坦血药浓度,计算药代动力学参数,并与单次灌胃给予奥拉西坦(200mg/kg)的对照组进行比较。结果奥拉西坦标准曲线方程为Y=0.0217X+0.1058(r=0.9992,n=7),质量浓度线性范围为2～100mg/L;低、中、高3种质量浓度的方法回收率分别为(102.25±8.51)%,(96.29±2.76)%和(98.14±1.62)%,日内及日间精密度的RSD均小于5.42%。对照组与试验组主要药代动力学参数,半衰期(t1/2)分别为(2.807±0.8751)h和(3.231±1.019)h,峰浓度(Cmax)分别为(52.80±16.94)mg/L和(47.33±8.317)mg/L,0～12h药时曲线下面积(AUC0-12h)分别为(257.2±77.84)mg.h/L和(258.9±67.30)mg.h/L,组间比较无显著性差异。结论酮康唑对大鼠体内奥拉西坦的药代动力学无显著影响。     

木兰脂素在大鼠体内的药动学研究

目的:研究木兰脂素在大鼠体内的药动学特征。方法:采用高效液相色谱(HPLC)法。色谱柱为Kromasil C18,流动相为乙腈-四氢呋喃-水(39∶1∶60),流速为1.0 ml/min,检测波长为278 nm,柱温为35℃,进样量为20μl。8只Wistar大鼠于给药[10mg(生药)/kg]前及给药后0.25、0.5、0.75、1、1.5、2、4、8、12、20 h尾静脉断尾取血测定血药浓度,采用DAS2.1.1软件计算药动学参数。结果:木兰脂素检测质量浓度线性范围为0.05~10.00μg/ml(r=0.999 5),精密度、稳定性试验的RSD均小于13%(n=6),方法回收率为97.32%~102.15%(n=6),提取回收率为84.63%~90.02%(n=6)。木兰脂素在大鼠体内t1/2α为(0.48±0.22)h,t1/2β为(7.96±2.57)h,CL/F为(0.09±0.032)L/(h·kg),AUC0-20 h为(944.43±212.83)mg·h/L。结论:本方法精密度、稳定性、准确度均符合生物样品测定要求。木兰脂素在大鼠体内AUC0-20 h与剂量呈良好的线性关系,过程符合二室模型。     

大黄酸在Beagle犬体内的毒代动力学研究

目的大黄酸为防治糖尿病肾病的新型药物,是大黄游离蒽醌衍生物的单体之一。在本研究中通过获得Beagle犬经口给予大黄酸后体内的毒代动力学信息,为临床安全用药提供参考依据。方法建立HPLC-荧光分析方法,采用与长期毒性试验相同的剂量设置(35、111和350mg/kg)进行毒代动力学研究,每组6只动物,雌雄各半,在给药第一天、连续给药26周(第182天)和连续给药39周(第273天)时进行毒代动力学试验,测定不同时间点的血浆大黄酸浓度,统计矩方法估算大黄酸在犬体内的毒代动力学参数。结果犬方法学验证该分析方法可靠,符合生物样品分析要求。犬经口给35、111和350mg/kg大黄酸第1天时,Cmax分别为(19.48±2.36)、(45.11±13.26)和(77.89±2.48)mg/L,AUC分别为(105.1±9.561)、(227.5±44.2)和(506.6±133.3)mg/(L.h)。给药26周时,Cmax分别为(23.96±3.36)、(50.85±3.31)和(80.98±3.58)mg/L,AUC分别为(128.1±32.0)、(270.8±27.4)和(591.4±24.2)mg/(L.h)。给药39周时,Cmax分别为(30.64±5.084)、(53.30±6.31)和(84.52±4.41)mg/L,AUC分别为(141.4±26.1)、(241.1±29.9)和(600.6±97.5)mg/(L.h)。结论在研究的剂量范围内,大黄酸在犬体内的毒代动力学过程是基本一致的,各剂量间AUC及Cmax的比例均接近1∶2∶4。对于同一剂量,单次给药和多次给药后的AUC和Cmax没有显著性改变。说明大黄酸在犬体内蓄积程度较轻。     

青天葵中鼠李柠檬素在大鼠体内的药代动力学研究

目的 研究青天葵中鼠李柠檬素在大鼠体内的药代动力学特征.方法以甲醇一乙腈-0.2％磷酸水溶液（30∶35∶35）为流动相,血浆样品经10％三氯乙酸沉淀蛋白后,采用高效液相色谱法测定鼠李柠檬素的血药浓度.采用DAS 2.1.1药代动力学软件计算鼠李柠檬素的主要药代动力学参数.结果 鼠李柠檬素质量浓度在0.05～10.00 μg/mL范围内与峰面积线性关系良好（r=0.9993）,回收率为98.1％ ～ 101.1％,日内和日间RSD均小于11％.鼠李柠檬素大鼠体内符合二室模型,主要药代动力学参数峰浓度（Cmax）为（875.37±65.53）μg/L,药物消除半衰期（t1/2β）为（8.993±2.568）h,0 ～24h药时曲线下面积（AUC0-24）为（4929.159±589.652）μg· h/L,0～∞药时曲线下面积（AUC0-x）为（5 945.567±612.985）μg·h/L.结论鼠李柠檬素的药代动力学研究结果为青天葵药材的质量评价奠定了良好基础.     

甲氨蝶呤在抑郁SD大鼠体内药代动力学

目的 研究抑郁大鼠抗肿瘤药物甲氨蝶呤(MTX)的药代动力学.方法 对抑郁组大鼠连续8 w给予慢性不可预见性温和应激建立抑郁实验动物模型.采用荧光偏振免疫法(FPIA)测定SD大鼠给药后0.083、0.5、1、2、4、8、12 h各时间点血浆中MTX浓度,采用DAS药代动力学软件计算相应药代动力学参数.结果 甲氨蝶呤在抑郁组大鼠和对照组大鼠体内药代动力学主要参数:Cmax分别为(8.10±0 99)和(7.99±1.04) μmol/L;t1/2分别为(2.11±0.24)和(2.24±0.32) h;AUC0→∞分别为(13.92±3.46)和(13.73±1.55) μmol·h·L-1;MRT0→∞分别为(1.99±0.45)和(2.15±0.44) h;CL分别为(0.13±0.03)和(0.14±0.04) L/h,显示甲氨蝶呤在抑郁组和对照组大鼠体内药代动力学参数基本一致,两组数据没有显著性差异.结论 抑郁大鼠甲氨蝶呤体内代谢动力学与正常大鼠药代动力学相近.     

奥硝唑片人体生物等效性研究

目的比较口服奥硝唑片试验制剂与国产上市制剂的药代动力学参数,进行生物利用度和生物等效性评价。方法开放、随机、单次给药、双周期交叉临床研究。共20例健康受试者。结果试验制剂和参比制剂的药代动力学结果:T1/2分别为(17.010±2.682)h和(17.446±2.519)h;Tmax分别为(1.550±0.759)h和(1.250±0.526)h;Cmax分别为(9.476±1.083)μg/μL和(9.592±1.251)μg/μL;AUC0-t分别(225.604±44.327)μg/(μL?h)和(213.880±43.834)μg/(μL?h);AUC0-∞分别为(231.269±48.014)μg/(μL?h)和(219.655±46.518)μg/(μL?h)。试验制剂对于参比制剂的平均相对生物利用度F值(106.9±15.4)%。两种制剂的AUC0-t、AUC0-∞及Cmax经对数转换后双单侧t检验结果P<0.05,接受两种制剂生物等效的假设。90%置信区间的计算结果:Cmax为93.7%¹04.5%,AUC0-t为100.0%104.5%,AUC0-t为100.0%¹12.1%,AUC0-∞为99.7%112.1%,AUC0-∞为99.7%¹11.9%,按照生物等效性判定标准,可判定两种制剂生物等效。结论两制剂间无显著性差异,两制剂具有生物等效性。适用与Ⅰ期临床研究。     

多烯紫杉醇在乳腺癌患者体内的药代动力学研究

目的研究多烯紫杉醇在乳腺癌患者体内的药代动力学。方法 10例乳腺癌患者采用多烯紫杉醇75 mg·m~(-2)静脉滴注1 h化疗,在化疗后不同时间采集血液标本,用HPLC法测定多烯紫杉醇血药浓度,用DAS 3.0软件计算药代动力学参数。结果多烯紫杉醇的血浆药物峰浓度Cmax均值为(3.345±1.05)mg·L~(-1),血药浓度-时间曲线下面积AUC0~12 h均值为(3.247±0.91)mg·h·L~(-1),消除半衰期t1/2均值为(9.602±3.72)h,清除率CL均值为(18.718±3.84)L/(h·m)-2。药动学参数在患者个体间存在较大差异。结论多烯紫杉醇在乳腺癌患者体内的药代动力学存在较大个体差异,提示在临床用药时需要监测多烯紫杉醇的血药浓度,进行个体化给药。     

肾功能异常患者司帕沙星的药代动力学

目的观察司帕沙星在肾功能异常患者体内的药代动力学特征。方法用高效液相色谱法测定10例住院患者单剂量和多剂量口服司帕沙星后血清和尿药物浓度,并计算药代动力学参数。结果经PKBP -N1 药代动力学软件模拟和计算,司帕沙星的药物动力学符合一级吸收二室开放模型,主要药动学参数 :单剂量T1/2(ka)=(1.02±0.22)h,T1/2(β)=(15.73±3.20)h,Tpeak=(3.88±0.75)h,Cmax =(0.59±0.17)mg·L-1,AUC0 -∞=(11.25±2.13)mg·h·L -1,尿中24h原形药物排除率为(10.58±1.47) %;多剂量T1/2(ka) =(1.25±0.27)h,T1/2(β)=(16.90±4.13)h,Tpeak=(4.18±0.78)h,Cmax =(0.79±0.21)mg·L-1,AUC0～∞=(13.34±2.25)mg·h·L-1,尿中24h原形药物排出率为(11.08±1.94) %。多剂量Cmax 和AUC明显高于单剂量(P<0.05),蓄积因子为1.19。结论中度肾功能异常不改变司帕沙星的药代动力学参数。     

头孢丙烯分散片在中国健康人体的药代动力学

目的研究头孢丙烯分散片在中国健康人体的药代动力学。方法 10名中国健康受试者,男女各半,单剂量口服头孢丙烯分散片500 mg。用高效液相色谱法同时测定血浆中顺式和反式头孢丙烯的浓度;用DAS 2.0药代动力学程序计算药代动力学参数。结果头孢丙烯的主要药代动力学参数:Cmax为(9.62±1.29)mg.L-1,Tmax为(1.30±0.35)h,t1/2(ke)为(1.32±0.15)h,V为(34.40±5.48)L,CL为(18.16±2.96)L.h-1,AUC0-10为(27.68±4.45)mg.h.L-1,AUC0-∞为(28.22±4.70)mg.h.L-1。结论头孢丙烯在人体内符合一级吸收的一室模型。     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg.kg) or i.p. (50 mg.kg) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) l.h. kg in the male rat and 10.6 (95% CI: 7.5, 15.0) l.h. kg in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p 0.001) in plasma obtained from the male (8.8 2.0%) compared with the female rat (11.7 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg x kg(-1)) or i.p. (50 mg x kg(-1)) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) 1 x h(-1) x kg(-1) in the male rat and 10.6 (95% CI: 7.5, 15.0) 1 x h(-1) x kg(-1) in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was approximately 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p < 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p < 0.001) in plasma obtained from the male (8.8 +/- 2.0%) compared with the female rat (11.7 +/- 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

Interindividual variability in metabolic activation in humans in vivo

In assessing interindividual variability in metabolic activation, the toxic metabolite is often too unstable for conventional analysis. Possible alternatives include a stable product of the reactive metabolite e.g. cysteinyl derivatives of N-acetyl-4-benzoquinoneimine, the toxic metabolite of paracetamol, adducts with DNA or protein, and indirect measurement of the activity of the enzyme(s) producing the active metabolite. An example of the last approach is the use of furafylline, a highly specific inhibitor of human CYP1A2, to determine the extent of the metabolic activation of the cooked food mutagens PhIP and MeIQx. The extent of inhibition, determined from levels of unchanged amine in urine, is an indirect measure of the activity of the activation pathway. Further refinement of this approach, allied to improved measures of the biological process of interest should prove of value in evaluating interindividual variability and its role in the risk assessment process.     

Theophylline kinetics in peripheral tissues in vivo in humans

Several biochemical and cellular effects have been described for methylxanthines under in vitro conditions. However, it is unknown, whether threshold concentrations required to exert these effects are attained in target tissues in vivo. We therefore employed the microdialysis technique for measuring theophylline concentrations in peripheral tissues under in vivo conditions.Following in vitro and in vivo calibration, microdialysis probes were inserted into the medial vastus muscle and into the periumbilical subcutaneous adipose layer of healthy volunteers. Following single oral dose administration of 300 mg or i.v. infusion of 240 mg theophylline, in vivo time courses of theophylline concentrations were monitored in tissues and plasma. Major pharmacokinetic parameters (c_max, t_max, AUC) were calculated for plasma and tissue time courses. The mean AUC_tissue /AUC_plasma-ratio was 0.56 (p.o.) and 0.55 (i.v.) for muscle and 0.55 (p.o.) and 0.72 (i.v.) for subcutaneous adipose tissue.We conclude that microdialysis provides important information on the distribution and the tissue pharmacokinetics of theophylline.Abbreviations FPIA Fluorescence polarisation immuno assay - AUC Area under the curve - t_max Time to peak concentration - c_max Peak concentration     

休克时血中氧自由基的变化

本实验测定10名休克患者血浆和红细胞的丙二醛(MDA)、血浆总抗的氧化活性(AOA)的含量。结果表明:休克病人红细胞膜和血浆 MDA 含量(4.298±0.722;5.348±0.834)与对照组(3.235±0.682;4.356±1.081)比较明显增高(P<0.05);血浆 AOA(39.65±7.858)与对照组(48.21±10.81)比较明显降低(P<0.01)。提示:休克时,患者机体内自由基反应增强是引起组织细胞损伤的原因之一。     

Changes in angiopoietin expression in glomeruli involved in glomerulosclerosis in rats with daunorubicin-induced nephrosis

AIM: To study the potential pathological role of endogenous angiopoietins in daunorubicin-induced progressive glomerulosclerosis in rats. METHODS: Seventy male Wistar rats were allocated randomly into a daunorubicin group (DRB; n=40) or a control group (n=30). The rats in the DRB group were injected with DRB (15 mg/kg), in their tails. Subsequently, at intervals of 1, 2, 4, 6, 8, and 12 weeks, 5 male Wistar rats in each group were chosen randomly for 24 h urinary protein quantitative measurements (24 h UPQM), and determination of plasma tumor necrosis factor alpha (TNF-alpha), angiopoietin-1 (Ang1), and angiopoietin-2 (Ang2) levels. Kidney sections were examined by electron microscopy, Periodic Acid Schiff (PAS) staining, immunohistochemical staining and in situ hybridization histochemistry. RESULTS: As glomerulosclerosis progressed in the DRB group, expression of Ang1 mRNA and protein in glomeruli decreased and expression of TNF-alpha protein, Ang2 mRNA and protein in glomeruli increased. Expression of Ang1 mRNA and protein in glomeruli were negatively correlated with 24 h UPQM, Fn protein expression, and mean area of extracellular matrix (MAECM). In comparison, expression of Ang2 mRNA and protein in glomeruli were positively correlated with 24 h UPQM, Fn protein expression and MAECM; furthermore, there was a positive correlation between plasma Ang2 and 24 h UPQM. Plasma TNF-alpha and expression of TNF-alpha in glomeruli were positively correlated with expression of Ang2 mRNA and protein in glomeruli. There was a negative correlation between Ang1 protein expression and Ang2 protein expression in glomeruli. CONCLUSION: During DRB-induced glomerulosclerosis, podocyte injury led to a shift in the balance of Ang1 and Ang2 in glomeruli. Increased TNF-alpha in plasma and glomeruli may upregulate Ang2 expression in glomeruli. Elevated Ang2 in both plasma and glomeruli may mediate protein permeability through the glomerular filtration barrier. Moreover, local expression of Ang2 may facilitate the progress of glomerulosclerosis by upregulating a component expression of extracellular matrix.     

Trichinellosis in immigrants in Switzerland

We describe a case of trichinellosis diagnosed at the Division of Infectious Diseases, Hospital of Lugano, in January 2009. This case was associated with a cluster of cases and was traced to the consumption of contaminated meat after a wild boar hunt in Bosnia.