猕猴硬膜外及静脉注射 [~(125)I]虎纹毒素-1的药代动力学(英文)

目的　研究与比较猕猴硬膜外 (ed)及静脉 (iv)注射虎纹毒素 1后的药代动力学过程。方法　Iodogen法标记虎纹毒素 1 ,按 0 388MBq·kg- 1 的剂量向猕猴第 3和第 4腰椎之间硬膜外腔及静脉注射标记后虎纹毒素 1 ,用反相高效液相色谱检测猴血清中的药物放射性活度 ;γ 计数仪检测猴第 3和第 4腰椎硬膜外腔的药物放射性活度。结果　制备了具有生物活性的 [1 2 5I]虎纹毒素 1。硬膜外给药 1 0min后 ,给药部位局部硬膜外腔的药物放射性占总给药量的0 38,说明硬膜外给药是成功的 .硬膜外及静脉给药后 ,血药浓度分别在 30min和 2min达峰 ,分别为 (0 70± 0 0 4 )MBq·L- 1 和 (4 98± 0 58)MBq·L- 1 。两种给药途径的药时曲线不同 :猕猴硬膜外和静脉给药后 ,末端T12 分别为(1 0 36± 0 2 7)h和 (1 1 0 3± 1 1 6)h ;ClS 分别为 (1 2 9±0 0 7)L·h- 1 ·kg- 1 和 (1 2 5± 0 2 3)L·h- 1 ·kg- 1 ,硬膜外给予 [1 2 5I]HWTX 1的绝对生物利用度 (95± 5) %。结论　硬膜外和静脉两种给药方式下 ,[1 2 5I]虎纹毒素 1在猕猴体内的药代动力学过程具有差异性 ,两种给药方式下 [1 2 5I]在猕猴体内的分布与吸收特点对于虎纹毒素 I的临床药效学和毒理学研究提供了参考数据。     

大鼠硬膜外和静脉注射虎纹毒素-Ⅰ后的组织分布

目的 比较大鼠硬膜外(ed)和iv ［¹²⁵I］标记虎纹毒素-Ⅰ(［¹²⁵I］HWTX-Ⅰ)后分布的差异。方法 Iodogen法制备［¹²⁵I］HWTX-Ⅰ，膈神经-膈肌法测定生物活性。反相高效液相色谱法鉴定放射化学纯度，三氯醋酸沉淀法测定放射性药物浓度。结果 ［¹²⁵I］HWTX-Ⅰ生物活性标记前后相近，放射化学纯度为98.5%。给药后2 h，ed组椎管局部放射性明显高于iv组(P<0.05)，ed和iv后组织放射性分别在2 h和10 min达峰值。泌尿系统放射性含量最高，脂肪、肌肉和脑放射性最低。放射性主要经尿排泄。结论 ed后椎管局部放射性高，维持时间较长，血清峰浓度较iv组低，有利于发挥局部镇痛作用，减少全身副作用。     

大鼠硬膜外和静脉注射虎纹毒素-Ⅰ后的组织分布

目的　比较大鼠硬膜外 (ed)和iv [12 5I]标记虎纹毒素 Ⅰ ([12 5I]HWTX Ⅰ )后分布的差异。方法Iodogen法制备 [12 5I]HWTX Ⅰ ,膈神经 膈肌法测定生物活性。反相高效液相色谱法鉴定放射化学纯度 ,三氯醋酸沉淀法测定放射性药物浓度。结果[12 5I]HWTX Ⅰ生物活性标记前后相近 ,放射化学纯度为 98.5 %。给药后 2h ,ed组椎管局部放射性明显高于iv组 (P <0 .0 5 ) ,ed和iv后组织放射性分别在 2h和 10min达峰值。泌尿系统放射性含量最高 ,脂肪、肌肉和脑放射性最低。放射性主要经尿排泄。结论　ed后椎管局部放射性高 ,维持时间较长 ,血清峰浓度较iv组低 ,有利于发挥局部镇痛作用 ,减少全身副作用。     

[~(125)I]西夫韦肽在大鼠体内的药代动力学

目的为临床上合理安全地应用西夫韦肽提供药代动力学资料。方法Iodogen法制备[125I]西夫韦肽,大鼠单次给[125I]西夫韦肽后,三氯醋酸(TCA)沉淀法测定血浆或组织中的放射性含量。结果大鼠单次sc0.8,2.4,7.2mg·kg-1[125I]西夫韦肽后,AUC分别为10.6,32.2和112.3mg·h·L-1;达峰时间在1.40~4.60h之间,吸收较为缓慢;t1/2(ke)分别为7.39,4.53,13.84h;血浆清除率相近,分别为0.44,0.70和0.50L·h-1;TCA法测定大鼠sc给药[125I]西夫韦肽组织分布,放射性分布特点为泌尿系统和胃肠道系统浓度最高,血浆其次,脑组织和脂肪组织内浓度最低。结论大鼠sc[125I]西夫韦肽后,在给药剂量范围内呈线性动力学。TCA沉淀法测得泌尿系统和胃肠道系统放射性最高。[125I]西夫韦肽主要经肾脏排泄。     

[~(125)I]Spiro-I脑靶向脂质体在小鼠体内分布(英文)

研究[125 I]Spiro-I经长循环脂质体(SSL)和脑靶向脂质体(SSTL)包载后的组织分布, 尤其考察其脑摄入。采用薄膜超声分散法制备[125 I]Spiro-I脂质体, RMP-7通过共价键连在DSPE-PEG上进一步形成靶向脂质体。[125 I]Spiro-I-SSL及 SSTL的包封率分别为97.47%±4.01%, 93.02%±2.98%, 粒径分别为(66.47±0.76) nm, (71.40±0.45) nm。给药后, [125 I]Spiro-I迅速从血液中清除, 长循环组延长了药物在血液中的保留时间, RMP-7提高了[125 I]Spiro-I的脑摄取量。[125 I]Spiro-I-SSTL组的AUC较游离药物组提高了1.52倍。SSTL有望拓展显像剂在中枢神经系统的应用。     

~(125)Ⅰ标记-萃取法研究大鼠血浆中PEG-Dipeptide-TNF-α的药代动力学

目的:建立提取大鼠血浆中总PEG的方法,并研究PEG-Dipeptide-TNF-α结合物的在大鼠体内药代动力学。方法:采用125I同位素标记PEG-Dipeptide-TNF-α,利用有机溶剂氯仿萃取血浆中总PEG量,两相体系分光光度法进行验证,放射免疫γ计数器检测萃取物放射性计数,并用3P87药动学软件进行曲线拟合并计算参数。结果:血浆样品冷冻干燥后用氯仿提取,两相体系分光光度法检测结果为高、中、低3个浓度样品的相对回收率在100%附近,日内精密度RSD均小于3%,空白血浆中的内源性物质不干扰已知放射数的样品。3P87药动学软件计算的结果显示,TNF-α和PEG-Dipeptide-TNF-α半衰期(t1/2)分别为0.31和21.22h,表明新型的PEG修饰技术可以延长的TNF-α半衰期。结论:本方法建立了血浆中总PEG的提取方法,专属性高,分离完全,操作简单,成本低廉,符合生物等效性指导原则关于生物样品分析方法的基本要求。     

重组人纤溶酶原Kringle 5的~(125)I标记及其体内代谢

目的:探讨放射性碘标记纤溶酶原Kringle 5(K 5)的生物学活性及其体内药代动力学。方法:采用基因工程方法制备重组人纤溶酶原Kringle 5(rhK 5),以小剂量Iodogen多次重复标记法标记rhK 5,细胞增殖抑制试验和亲和力试验检测125I-rhK 5活性,并研究其在大鼠体内的药代动力学。结果:125I-rhK 5的标记率为86%,放射化学纯度为96%。细胞增殖抑制试验表明,125I-rhK 5的生物活性与未标记rhK 5相当。大鼠单次股静脉注射2μg125I-rhK 5后,血药浓度-时间曲线符合两室模型,T 1/2α为(0.31±0.03)h,T 1/2β为(14.48±0.73)h,AUC为(436.58±34.6)ng.h.m-l 1。结论:小剂量Iodogen多次重复125I标记不影响rhK 5的生物学活性1。25I-rhK 5大鼠体内单次静脉注射的药代动力学符合两室模型,半衰期约为15h。125I-rhK 5为肿瘤的显像和靶向治疗奠定了基础。     

PEG-EPO在大鼠体内的药代动力学研究

目的：探讨聚乙二醇化促红细胞生成素（PEG-EPO）在大鼠体内的药代动力学。方法：采用放射性核素125I对PEG-EPO进行标记,测定高、中、低（27,9,3μg·kg^-1）3个剂量组大鼠静脉注射125I-PEG-EPO后不同时间血浆中药物的放射性浓度,用DAS软件拟合放射性浓度一时间曲线,并计算药代动力学参数。结果：低、中、高3个剂量组给药后0．017h（1min）血药浓度分别为（24．800±3．535）,（80．971±16．368）,（269．620±26．360）ng·mL^-1,与剂量呈正相关,r=0．9998;血中药物消除半衰期五例分别为（27．22±3．67）,（28．40±1．61）,（33．12±1．83）h,随剂量的增加无显著变化;AUC0-120h分别为（69．22±7．13）,（218．77±34．57）,（470．424-65．88）ng·h·mL^-1,与剂量呈正相关,r=0．9909。结论：PEG-EPO在大鼠体内的代谢过程呈线性动力学特征,符合二室开放模型。     

大鼠静脉注射丹参酚酸B后的药代动力学研究

目的:建立丹参酚酸B的反相高效液相色谱分析方法,并对其在大鼠体内的药代动力学行为特性进行全面的分析研究。方法:生物样品采用液-液萃取方法,以Hypersil C18ODS色谱柱(200 mm×4 .6 mm,5μm) ,柱温40 ℃,流动相:乙腈水=20 80(含0 .25 mol/L乙酸胺) ,用磷酸调pH至4 .0 ,流速:1 .0 mL/min;紫外检测波长:328 nm。结果:鼠尾静脉给予丹参酚酸B1 .6、3 .2、6 .4 mg/kg后,结果显示鼠α相半衰期为(3 .1±0 .1) min,β相半衰期为(31 .5±3 .2) min。大鼠尾静脉给予丹酚酸B后,组织中浓度依次为(高→低) :心、肝、肺、小肠、肾脏、脾、胃、卵巢和脑组织。丹参酚酸B在粪便和尿中24 h及胆汁中2 h的累积排泄百分数分别约为1.43 %、0.77 %及8 .03%。丹参酚酸B人血浆蛋白结合率和大鼠血浆蛋白结合率分别为89 .2 %±1 .8 %和92 .5 %±1 .5 %。结论:本法准确、稳定、灵敏度高,适合生物样品中丹参酚酸B的分析。丹参酚酸B在大鼠体内消除速度快,血浆蛋白结合率较高,胆汁为其主要排泄途径。     

静脉注射用乌苯美司脂肪乳制备及药代动力学研究(英文)

脂肪乳作为难溶性药物的载体受到广泛的关注。乌苯美司作为一种水难溶性药物,市场上没有可供注射用剂型。本文利用SolEmuls技术制备注射用乌苯美司脂肪乳,采用单因素设计优化处方,得到的乌苯美司脂肪乳高压灭菌前后均比较稳定。制备的乌苯美司脂肪乳平均粒径在200nm左右,zeta电位为-44mV,体外释放行为符合双相动力学方程:100-Q=75.27e~(0.369t)+15.94e~(-0.0324t),R_α=0.9863,R_β=0.9878。药代动力学实验表明乌苯美司脂肪乳和静注乌苯美司混悬液药代动力学参数只有t_(1/2)有显著性差异。实验结果表明,对于水难溶性药物乌苯美司来说,静脉注射用脂肪乳可以作为一种安全有效的给药方式。     

Population pharmacokinetics of oxycodone in plasma and cerebrospinal fluid after epidural and intravenous administration

Objectives: To establish the first plasma and cerebrospinal fluid (CSF) oxycodone population pharmacokinetic (PopPK) model after epidural (EPI) and intravenous (IV) oxycodone administration.

Methods: The study was conducted with 30 female subjects undergoing elective gynecological surgery with epidural analgesia. A parallel single dose of EPI oxycodone with IV placebo (EPI group; n = 18) or IV oxycodone with EPI placebo (IV group; n = 12) was administered. An epidural catheter for drug administration was placed at T12/L1 and a spinal catheter for CSF sampling at L3/4. Plasma and CSF for oxycodone analysis were frequently collected. A PopPK model was built using the NONMEM software package.

Results: Plasma and CSF oxycodone concentrations were evaluated using separate central plasma and CSF compartments and separate peripheral plasma and CSF compartments. Epidural space served as a depot compartment with transfer to both the plasma and CSF central compartments. The population parameters for plasma clearance and apparent distribution volumes for central and peripheral compartments for plasma and CSF were 37.4 L/h, 90.2 L, 68.9 L, 0.035 L (fixed based on literature), and 0.039 L, respectively.

Conclusion: A PopPK model was developed and found to precisely and accurately describe oxycodone time-concentration data in plasma and CSF.     

Pharmacokinetics of different epidural sites of morphine administration

Summary In order to determine the rate and degree of redistribution of morphine within the cerebrospinal fluid (CSF), and whether it was affected by the site of and volume of the injection, morphine was given to 23 elderly patients undergoing thoracotomy — in 10 ml saline in the lumbar epidural interspace (n=5), in 10 ml saline in the thoracic epidural interspace (n=5), in 2 ml saline in the thoracic interspace (n=8) and in 10 ml saline in the lumbar epidural interspace (n=5).The plasma concentration of morphine in all patients was comparable and was much lower than in the CSF. The CSF morphine concentration, measured as the area under the CSF concentration curve (AUC), the maximal CSF concentration (C_max) and the time to reach maximal CSF concentration (t_max), varied between the four groups. The variation was related to the site of the injection; the AUC and C_max were lower and t_max appeared later after thoracic than lumbar injection. Lumbar CSF morphine concentrations were further reduced by thoracic epidural injection of morphine in a small as compared to a large volume. The permeability of the dura to morphine was not influenced by the volume used. The results show that morphine is not homogenously distributed within the CSF. The availability of morphine to CSF from the epidural space is not altered by the injection volume, but the drug remains more localized in CSF after epidural injection of morphine in a small volume. The findings imply that epidural injection of morphine in a small volume at a site of nociceptive input should evoke spinal analgesia with least risk of supraspinally mediated side effects.     

人工合成胸腺素α1在猴体内静脉注射的药动学研究

目的：研究人工合成胸腺素α1（sTα1）在猴体内i.v.的血药浓度-时间曲线、药动学参数特点。方法：用竞争性ELISA法测定sTα1在猴体内i.v.后血清中的药物浓度,用DAS药动学统计软件进行血药浓度-时间曲线拟合及药动学参数计算。结果：猴i.v.sTα11.2mg/kg的药动学特征符合二室开放模型,呈一级动力学消除。结论：猴i.v.sTα1的药动学行为符合二室一级消除。     

重组人干扰素α2a在小鼠和大鼠体内i.v.和i.m.的药动学研究

目的：研究rj-干扰素α2a（rh—IFNα2a）在小鼠和大鼠体内i．v．和i．m．的血药浓度-时间曲线、药动学参数和分布、排泄特点。方法：用双抗体夹心ELISA法测rh—IFNα2a在小鼠和大鼠体内i．v．和i．m．后血清、胆汁、尿液及组织中的药物浓度，用DAS药动学统计软件进行血药浓度-时间曲线拟合及药动学参数计算，并结合免疫组织化学技术研究rh—IFNα2a的组织分布特点。结果：Rh—IFNα2ai．v．和i．m的药动学行为分别符合二室和一室开放模型，呈一级动力学消除；rh．IFNα2a主要分布在肾、肺组织中；rh-IFNα2a36h尿累计排泄量为0．121％，胆汁累计排泄量为0．247％。结论：I．v．、i．m．rh—IFNα2a的药动学行为分别符合二室一级消除、一室一级消除。     

Comparative pharmacokinetics of cefuroxime lysine after single intravenous,intraperitoneal, and intramuscular administration to rats

Aim:

To compare the pharmacokinetic parameters of cefuroxime lysine, a new second-generation of cephalosporin antibiotics, after intravenous (IV), intraperitoneal (IP), or intramuscular (IM) administration.

Methods:

Twelve male and 12 virgin female Sprague-Dawley rats, weighing from 200 to 250 g, were divided into three groups (n=4 for each gender in each group). The rats were administered a single dose (67.5 mg/kg) of cefuroxime lysine via IV bolus or IP or IM injection. Blood samples were collected and analyzed with a validated UFLC-MS/MS method. The concentration-time data were then calculated by compartmental and non-compartmental pharmacokinetic methods using DAS software.

Results:

After IV, IP or IM administration, the plasma cefuroxime lysine disposition was best described by a tri-compartmental, bi-compartmental or mono-compartmental open model, respectively, with first-order elimination. The plasma concentration profiles were similar through the 3 administration routes. The distribution process was rapid after IV administration [t_1/2(d), 0.10±0.11 h vs 1.36±0.65 and 1.25±1.01 h]. The AUMC_0–∞ is markedly larger, and mean residence time (MRT) is greatly longer after IP administration than that in IV, or IM routes (AUMC_0–∞: 55.33±20.34 vs 16.84±4.85 and 36.17±13.24 mg·h²/L; MRT: 0.93±0.10 h vs 0.37±0.07 h and 0.65±0.05 h). The C_max after IM injection was significantly higher than that in IP injection (73.51±12.46 vs 49.09±7.06 mg/L). The AUC_0–∞ in male rats were significantly higher than that in female rats after IM administration (66.38±16.5 vs 44.23±6.37 mg·h/L). There was no significantly sex-related difference in other pharmacokinetic parameters of cefuroxime lysine between male and female rats.

Conclusion:

Cefuroxime lysine shows quick absorption after IV injection, a long retension after IP injection, and a high C_max after IM injection. After IM administration the AUC_0–∞ in male rats was significantly larger than that in female rats.     

7例妇女应用布比卡因硬膜外阻滞后的药物动力学和药效学

采用HPLC法对7例妇女应用布比卡因硬膜外阻滞后的药物动力学(药动学)和药效学进行研究,数据用PKBP-N_1药动学程序包经IBM-PC计算机处理,结果符合血管外开放二室模型。T_p=19±8min;C_p=1.6±0.7μg/ml;T_((1/2)β)=166±59min;AUC=273±124μg/(min·ml);V_d=2.0±0.7L/kg。测得该药的作用完善时间和麻醉持续时间分别为21±3min和104±30min。手术期间未见明显不良反应。应用测得之药动学参数估算作用完善时和局麻持续时间的血药浓度.     

Pharmacokinetics of rec-hirudin in healthy volunteers after intravenous administration

The pharmacokinetics of recombinant hirudin (rec-hirudin, Ciba-Geigy, CGP 39 393) in healthy volunteers after iv administration was investigated on the basis of the data from five different studies. A total of 77 plasma profiles following a single iv bolus dose of either 0.1, 0.3, 0.5, or 1 mg/kg of rec-hirudin was used for the evaulation. Plasma concentrations and especially AUC were proportional to the dose. Kinetics of rec-hirudin after a bolus iv injection were best described by a three-compartment open model. Mean apparent terminal half-life was 2.8 hr and the total clearance 0.138 L/hr per kg.     

Pharmacokinetic profiles in rats after intravenous, oral, or dermal administration of dapsone.

Dapsone is a potent anti-inflammatory and antibacterial agent that has been used extensively in the oral treatment of leprosy and dermatitis herpetiformis. This study compared the pharmacokinetic profile of dapsone in rats given a single oral or i.v. 12 mg/kg dose (n = 8/group) or a single dermal application of 12 or 60 mg/kg (n = 12/group) in an aqueous gel application medium containing 10 or 25% diethylene glycol monoethyl ether (DGME). Blood samples (200 microl) were collected via tail vein from each rat and pooled at intervals up to the 24-h period. A terminal blood sample was collected by cardiac puncture from each animal. Plasma concentrations of dapsone were determined by liquid chromatography atmospheric pressure ionization tandem mass spectroscopy. There was no treatment-related overt toxicity observed in any of the animals. Peak levels were reached 1 h after oral dosing (4890 ng/ml), and 6 to 8 h after dermal application, with Cmax values of 1.62, 5.56, and 12.8 ng/ml, for 12 mg/kg at 10 or 25% DGME, and for 60 mg/kg at 25% DGME, respectively. Bioavailability was calculated at 78% after oral dosing and <1% after dermal application. Apparent elimination half-lives (t(1/2))s were similar after i.v. and oral dosing. Both the calculated area under the plasma concentration versus time curve up to 24 h and Cmax values were 3- to 4-fold higher in the dermal application group administered 12 mg/kg dapsone in 25 versus 10% DGME gel, whereas the calculated area under the plasma concentration versus time curve up to 24 h and Cmax values for the 60 mg/kg group were only 3.3- and 2.3-fold greater than those obtained after application of 12 mg/kg in 25% DGME. These results show that both systemic exposure and peak plasma concentrations of dapsone are minimized by dermal versus oral administration of the compound.