国产头孢哌酮药代动力学和药效学研究

文报告14例病人国产头孢哌酮的药代动力学与药效学研究结果。国产和进口头孢哌酮2g恒速静滴1h,血浓峰值分别为211μg/ml和252μg/ml。国产品V_n值为0.24L/kg,进口品为0.17L/kg(p<0.05),其余各项动力学参数无显著差异,药时曲线方程国产品为y=165.40e~(-2.3258t)+155.53e~(-0.2127t),进口品为y=145.93e~(-3.1223t)+230.99e~(-0.3199t)。国产品以双室模型模拟相关性为r=0.9669,败血症病人显效血浓为287±68μg/ml,呼吸道感染病人显放血浓为223±51μg/ml。产生毒副反应组与未产生毒副反应组血浓分别为295和178μg/ml(p<0.01)。     

利多卡因燐光分析法及其在药物动力学上的应用

利多卡因在pH3.4时能与金莲橙OOⅣ结合成复合物并溶于氯仿中,将提取的复合物还原,测还原金莲橙燐光,由此计算利多卡因的含量。本法可检测3ng利多卡因,用于血中利多卡因测定,重复性较好,可定量回收。 小鼠im(10mg/kg),狗iv(4mg/kg)利多卡因后,测血药浓度,经药物动力学分析为二室型,其血药浓度表达式为:小鼠:C_((μg/ml))=2.49e~(-0.00677t)+3.43e~(-0.0217t -7.14e~(-0.0892t)。犬:C((μg/ml))=2.03e~(-0.0142t)+2.68e~(-0.146t)     

〔~3H〕-藏花素在大鼠体内吸收、分布及排泄的初步研究

用[~3H]-藏花素大鼠灌胃,血药半对数浓度-时间曲线用残数法处理,符合线性开放二室模型。中心室药浓度时间方程为:C=-2.7642e~(-0.5330t)+0.5328e~(-0.2592t)+2.1813e~(-0.0085t),主要动力学参数:t(1/2)ka=1.30hr,t(1/2)α=2.675r,t(1/2)β=81.53hr,t_(max)=4.54hr,v_1=630.81ml,TBCL=5.36ml/hr。除睾丸外各脏器放射性浓度高峰均出现在给药后 4～6 hr,与血浆中t_(max)一致。给药后96h各脏器中仍残留有一定量的放射性。大鼠灌胃后放射性主要由粪与尿中排出,给药96hr后粪及尿中分别排出全部放射性的68.22％和17.29％。     

唐松草新碱两种剂型的药物动力学比较

本文研究了经乙醚提取看,由反相HPLC测定血样中唐松草新碱(TD)的方法。用该法研究和比较了TD多相脂质体(139-2)和TD盐酸液(72)两种剂型在小鼠体内的药物动力学行为和差异。所得血药浓度数据经PCNONLIN程序处理,结果表明,(139-2)和(72)单次尾静脉注射后的药时曲线均符合开放双隔室模型。其双指数方程分别为C=23.73e~(-0.1972t)+1.203e~(0.0294t)以及C=21.446e~(-0.536t)+4.356e~(-0.0623t)。其中α、β相半衰期分别为3.52、23.58min和1.293、11.12min。二因素方差分析表明,两种剂型的药物动力学过程有显著差异。质脂体使TD在血循环中维持较高的浓度和持续较长的时间。     

体内药物累积法研究白血康的表观药物动力学

采用体内药物累积法测定小鼠 ip 白血康后的体内过程和药动学参数,白血康在小鼠体内的过程符合二室开放模型,模型方程为:体存率%=87.1711e~(-1.0952t) 138.1771e~(-0.0272t),t_(1/2)α=0.6328h,t_1/2β=25.48h,k_(21):0.6821h~(-1),k_(12)=0.3966h~(-1),k_(10)=0.0437h~(-1),Vc=3.55L/kg.     

氨苄西林在新生儿的药物动力学

本文报告19例患儿应用氨苄西林以输液泵控恒速静滴与墨菲管滴入2种给药方法的药物动力学与药效学。按体重25-27mg/kg bid计算给药量,单剂(250mg)1h滴毕,12h给药1次。血药峰值分别为117μg/ml和224μg/ml(P<0.05)。药物动力学参数(V_d,Cl,AUC)有非常显著性差异(P<0.01)。恒速静滴药时曲线方程为y=112.61e~(-0.3186t);墨菲管摘入为y=211.36e~(-0.3310t);2组参数均用一室模型模拟,相关系数(r)均为0.9999。不良反应有皮疹等.     

高效液相色谱法测定人体血浆中头孢哌酮浓度及药动学研究

本文报道了用HPLC法对头孢哌酮(先锋必)在人体中药动学的研究以及血浆中药物浓度的测定。依次用乙腈、二氯甲烷沉淀血浆蛋白,取上清液直接进样。以ODS为固定相,甲醇:水:冰醋酸(300:700:1),用乙酸钠调pH至5.85为流动相,检测波长λ=254nm内标物为头孢拉定。头孢哌酮最低检出值1μg/ml,标准曲线y=1.2235x—0.005225,r=0.9998,线性范围2.5--800μg/ml,平均回收率为94.0±7.5%。本法对6名健康受试者体内药动学进行了研究,结果表明其处置过程符合线性二室模型,药时曲线方程C=173.20e~(-1.497t) 86.56e~(-0.2733t),人体内平均t_(1/2)β为2.6h。     

甲基橙皮甙的药物动力学研究

本文应用紫外分光光度法测定甲基橙皮甙的血药浓度。60mg/kg iV 后,家兔体内药时曲线是一房室模型。平均动力学参数(n=6)为C_0=337.2±76.46μg/ml。K=0.02004±0.007min~(-1)。t1/2=38.59±13.73min,V=501.0±131.5ml,AUC_0~∞=18100±5498min·μg/ml,C1=10.08±4.693ml/min,按静脉给药10倍剂量口服灌胃,未测得血药。表明其绝对生物利用度极低、     

国产头孢哌酮/舒巴坦复方制剂的人体药物动力学

目的研究国产头孢哌酮(CPZ)和舒巴坦(Sul)复方制剂在正常人体内的药物动力学.方法12名健康受试者恒速ivgtt2g国产或进口复方制剂(Sul、CPZ各1g),用RP-HPLC法分别测定CPZ和Sul的经时血药浓度.药-时数据用3P87程序拟合.结果药-时曲线符合二室开放模型.国产制剂单剂量ivgtt后,CPZ的AUC0→∞为(229.10±44.21)μg*h/ml,T1/2β为(2.20±0.49)h,MRT为(2.96±0.95)h,Cls为(4.7±0.9)L/h,Vc为(7.9±1.3)L;Sul的AUC0→∞为(65.90±6.71)μg*h/ml,T1/2β为(1.11±0.21)h,MRT为(1.53±0.40)h,Cls为(16.0±1.9)L/h,Vc为(15.7±4.6)L.方差分析显示主要药物动力学参数国产与进口制剂无统计学差异(P＞0.05).结论国产与进口复方制剂的药物动力学基本相似.     

头孢氨苄血药浓度的荧光法测定及药物动力学研究

本文研究了荧光法测定头孢氨苄的血药浓度及其药物动力学。实验结果表明,血清浓度在1～20μg/ml范围内,荧光强度与浓度有较好的线形关系,r=0.9975。回收率为94.7%±2.3%(n=5),CV=2.39%。浓度时间曲线(头孢氨苄0.5g,PO)显示为一室模型。平均药物动力学参数(n=8):Ka=1.7500(h~(-1)),K=0.7365(h~(-1)),T_(1/2)=0.9401(h),T_(max)=1.18(h),C_p=19.64(μg/ml),V_a/F=13568.2(ml)。     

氨甲喋呤多相脂质体的制备及其动物抑瘤活性和临床前药理学实验研究

采用融熔法制备了氨甲喋吟(MTX)多相脂质体,并进行了抑瘤活性、小鼠急性毒性、家兔亚急性毒性和安全性实验。结果表明多相脂质体剂型显著提高了 MTX 对小鼠 EC 和 L615瘤株的抑瘤活性。急性毒性实验结果表明 MTX 多相脂质体和 MTX 水溶液的 ivLD_(50)值无显著性差异。亚急性毒性实验表明 MTX 多相脂质体大剂量给药时可出现肝细胞变性坏死。安全性实验未见异常反应。     

Drug absorption behavior after periocular injections.

The purpose of this study was to investigate the absorption behavior of an ophthalmic drug injected in rabbit periocular tissues. After intracapsular, retrobulbar and palpebral conjunctival injections of 150 microl and 50 microl fluorescein isothiocyanate dextran (FITC-dextran, average molecular weight 11000), leakage of the dye into the tear fluid was dependent on the injection route and volume. After periocular injections (50 microl) of tilisolol, as a model beta-blocker, the concentrations in the tear fluid, blood, aqueous humor and vitreous body were determined by HPLC. Slight drug leakage was observed in the tear fluid after injections. The periocular injections showed a faster absorption and a higher area under the concentration-time curve (AUC) in the plasma and a lower AUC in the aqueous humor than those observed in instillation. They also showed a higher ratio of AUC of tilisolol in the vitreous body to AUC in the aqueous humor than that observed in the instillation. Among the periocular injections, retrobulbar injection showed the highest concentrations in the plasma and the lowest in the aqueous humor and vitreous body, while intracapsular injection showed the lowest in the plasma and the highest in the aqueous humor and vitreous body. Although the periocular injections showed a rapid systemic absorption of drug by a rich topical vasculature, it might be an effective approach to deliver the drug to the periocular tissues and vitreous body.     

Pharmacokinetic advantage of intraperitoneal injection of docetaxel in the treatment for peritoneal dissemination of cancer in mice

Intraperitoneal administration of docetaxel has been used to treat peritoneal dissemination of cancer, but its safety has not yet been confirmed. We have compared the pharmacokinetic behaviour of docetaxel after intravenous and intraperitoneal administration in CD-1-nu/nu mice bearing MKN45P, a gastric cancer variant line producing peritoneal dissemination. Docetaxel (8 mg kg(-1)) was intravenously or intraperitoneally injected into the mice and at designated times the drug concentration was measured in plasma, ascites fluid, and abdominal tissues (liver, kidney, intestine and spleen, solid cancer, and suspended free cancer). The pharmacokinetic behaviour of docetaxel was similar in control mice and cancer-bearing mice after administration via either route, except that the transfer of docetaxel from the abdominal cavity to systemic blood (plasma) was slower in cancerbearing mice than in control mice. As expected, the intraperitoneal drug concentration was much higher (approximately 100-fold) and was maintained for a longer time in the intraperitoneal injection group than in the intravenous injection group. The drug concentrations in peritoneal solid cancer tissue and suspended free cancer cells were also significantly higher for a longer time in the intraperitoneal injection group than in the intravenous injection group. The values of the plasma area under concentration-time curves (AUC) were similar for both administration routes. The ratio of AUC ascite/AUC plasma after intraperitoneal administration was higher than after intravenous administration. The drug concentration in abdominal organs after intraperitoneal injection was lower during the first 2 h, then became similar to those after intravenous injection. These results indicated that the intraperitoneal administration of docetaxel for peritoneal dissemination was likely to be an effective treatment method, without causing any increase in systemic toxicity.     

微分法计算一室模型药物静脉滴注的药动学参数

目的:建立一种根据血药浓度线性消除的微分特征计算静脉滴注一室模型药物动力学参数的新方法。方法:通过微分方法分析单次静脉滴注一室模型药物的动力学特征,求出消除速度常数k和表观分布容积V等药动学参数。结果:模拟计算结果表明,该法具有良好的准确性。结论:以微分法计算静脉滴注给药一室模型药物的药动学参数,具有计算便捷、结果准确的优点。     

Enhanced disappearance of drugs from plasma following polybrominated biphenyls.

Polybrominated biphenyls (PBBs) are potent stimulators of hepatic drug metabolism. The purpose of this investigation was to determine the effect of dietary exposure to PBBs on the disappearance of drugs from plasma in mice. To estimate hepatic function, plasma and hepatic concentrations of indocyanine green (ICG) and ouabain were determined at various times following intravenous injection of these drugs (ICG, 40 mg/kg; ouabain, 0.1 mg/kg). Two-week dietary exposure to PBBs did not affect body weight but resulted in a dose-dependent increase in liver weight. Plasma concentrations of ICG were significantly lower than control values 10 and 15 min following injection of ICG in mice fed 100, 150, and 200 ppm of PBBs. In addition, 60-min plasma ouabain concentrations in 100- and 200-ppm PBBs-fed mice were significantly lower than control values. PBBs induced enhanced disappearance of ICG from plasma correlated to significantly higher hepatic ICG content. This effect was similar to that produced by phenobarbital pretreatment (75 mg/kg/day for 4 days) in mice. When compared to controls, mice fed PBBs had significantly higher hepatic ouabain content 10 min following glycoside injection but significantly lower amounts in liver 30 and 60 min following injection. PBBs feeding did not alter ouabain LD50 values. These results demonstrate that PBBs enhance drug elimination from plasma.     

用生物鉴定法观察抗血吸虫新药吡喹酮在家兔体内的吸收、分布和排泄

用以血吸虫为标本的生物鉴定法,观察了抗血吸虫新药吡喹酮在家兔体内的代谢。自家免胃肠道的不同部位注入吡喹酮时,以小肠的吸收最好,直肠次之,而结肠和胃则较差。药物自小肠吸收后,周围静脉血浆的药浓度较门静脉的低10倍以上。家兔口服吡喹酮100mg/kg的血浆药浓度与皮下注射20mg/kg的相仿;肌肉注射吡喹酮20mg/kg的血浆药浓度较皮下注射的为高;若静脉注射相同剂量,则于注射完毕时虽有甚高的血药浓度值,但药物可迅速自血浆中消除。吡喹酮多次给药时无积蓄作用;若每4小时给药一次,连给3次,则可依次增加血浆的药浓度。家兔一次口服吡喹酮30分钟～4小时,以胃、小肠组织的含药量较高,肝、肾和脑等次之。给药后24小时,除胃和小肠外,其余脏器组织中的药物均已消除。此外,自服药兔的粪、尿中检获有生物活性的物质。     

Effect of aminophylline on tryptophan and other aromatic amino acids in plasma, brain and other tissues and on brain 5-hydroxytryptamine metabolism.

1 Aminophylline and other methylxanthines increase brain tryptophan and hence 5-hydroxytryptamine turnover. The mechanism of this effect of aminophylline was investigated. 2 At lower doses (greater than 100 mg/kg i.p.) the brain tryptophan increase could be explained by the lipolytic action of the drug, i.e. increased plasma unesterified fatty acid freeing plasma tryptophan from protein binding so that it became available to the brain. 3 Plasma unesterified fatty acid did not increase when aminophylline (109 mg/kg i.p.) was given to nicotinamide-treated rats but as both plasma total and free tryptophan rose, a tryptophan increase in the brain still occurred. 4 The rise in brain tryptophan concentration following the injection of a higher dose of the drug (150 mg/kg i.p.) could no longer be explained by a rise of plasma free tryptophan as the ratio of brain tryptophan to plasma free tryptophan rose considerably. Plasma total tryptophan fell and the plasma insulin concentration rose. 5 The increase of brain tryptophan concentration after injection of 150 mg/kg aminophylline appeared specific for this amino acid as brain tyrosine and phenyllanine did not increase. However as their plasma concentrations fell the brain/plasma ratio for all three amino acids rose. 6 The higher dose of aminophylline increased the muscle concentration of tryptophan but that of tyrosine fell and that of phenylalanine remained unaltered. The liver concentrations were not affected. 7 The aminophylline-induced increase of the ratio of brain tryptophan of plasma free tryptophan no longer occurred when the drug was given to animals injected with the beta-adrenoreceptor blocking agent propranolol or the diabetogenic agent streptozotocin. 8 The changes in brain tryptophan upon aminophylline injection may be explained by (a) increased availability of plasma tryptophan to the brain due to increased lipolysis and (b) increased effectiveness of uptake of tryptophan by the brain due to increased insulin secretion.     

微分法计算二室模型药物静脉推注的药物动力学参数

目 的建 立 一 种 根 据 血 药 浓 度 线 性 消 除 的 微 分 特 征 计 算 静 脉 注 射 双 室 模 型 药 物 动 力 学 参 数 的新方 法 。方法 通 过 微分 方法 分 析单 次静 脉 注射 双室 模 型药 物的 动 力学 特 征，求出 快 速处 置速 率 常数 （α）、慢 速处置速 率 常数 （β）、Ａ 、Ａ２ 等 混杂 参数 ，并 据此 计 算室 间的 转 运速 率常 数 ｋ１２、ｋ２１、ｋ１０，中 央室 分布 容 积 （Ｖ ）等主 要 的 药 １ １物动 力 学参 数。结 果 在 获得 混杂 参 数 α、β、Ａ 、Ａ２ 后，得到 Ｖ１、ｋ１２、ｋ２１、ｋ１０ 等主 要 药物 动力 学 参数 的计 算 方法 。模 １拟计 算 结果 表明 ，本法 具 有 良 好的 准 确 性 。结 论 以 静脉 推 注 血 药浓 度 的 微 分法 计 算 双 室 模型 药 物 的 药物 动 力学参 数 ，具 有计 算快 速 、结果 准 确的 优点 。     

The phenomenon and rationale of marked dependence of drug concentration on blood sampling site. Implications in pharmacokinetics, pharmacodynamics, toxicology and therapeutics (Part I)

At least 42 compounds have been reported to exhibit significant or marked blood sampling site dependence in concentration after dosing in humans and animals. The very high efficiency of uptake of drug by the poorly perfused sampling tissue (e.g. arm or leg) during its very short transit through the capillary (1 to 3 seconds) is mainly responsible for such a universal phenomenon. When marked arteriovenous concentration differences exist, their entire plasma (blood or serum) concentration-time profiles may resemble those obtained from completely different drugs or from different dosing rates. After an intravenous bolus injection, the reported maximal arteriovenous differences were 3240-fold for griseofulvin during the early distribution phase (arterial concentration being higher than venous, and 234% for procainamide during the terminal phase (venous concentration being higher). The reported maximal steady-state arteriovenous difference during infusion was 3.8-fold for glyceryl trinitrate (nitroglycerin), with the arterial level higher, due to metabolism and possible strong binding by sampling tissue. Interestingly, peak arterial plasma concentrations were usually achieved at about 0.5 minutes, while peak venous plasma concentrations generally occurred at 1 to 5 minutes after injection. Thus, the plasma concentration-time profile after an intravenous bolus injection actually resembles that predicted for a short term intravenous infusion, according to the classical instantaneous input hypothesis. Potential factors that may affect the degree of arteriovenous difference are here reviewed in detail. The implications of potential marked arteriovenous differences in pharmacokinetics, in pharmacokinetic/pharmacodynamic correlations or modelling, in toxicology, and in drug therapy are extensively discussed. Clinicians or scientists dealing with the determination and/or use of plasma concentration data should be fully aware of this problem. Many previous studies, based on the commonly accepted assumption that immediately or shortly after dosing plasma (blood) concentrations are essentially uniform throughout the blood circulation or the central (plasma) compartment, may require a reexamination. This is particularly important since the 'driving force' for distribution of a drug to various parts of the body for elimination, for accumulation or for producing a pharmacological or toxic effect, is its concentration in arterial blood, and not in venous blood drained from a poorly perfused tissue (venous blood may more accurately reflect drug concentrations in the poorly perfused sampling tissue itself). The present review probably represents the first of its kind ever reported in the literature. It is hoped that the review will increase the awareness of this very fundamental and important subject matter among our readers, and may also stimulate further studies or discussions.     

Plasma concentrations of diazepam and its metabolites after peroral, intramuscular, and rectal administration. Correlation between plasma concentration and sedatory effect of diazepam.

Plasma levels of diazepam, N-demethyldiazepam and free oxazepam were measured gaschromatographically in ten healthy volunteers after 5 mg of diazepam perorally, intramuscularly and rectally (with three different kinds of suppositories). The best absorption of diazepam was found after peroral administration. After an intramuscular injection a delayed absorption with low plasma concentrations of diazepam was found. The basal component of a diazepam suppository seems to have a great effect on the rectal absorption of diazepam. Two of the three different kinds of diazepam suppositories caused higher plasma diazepam concentrations than the intramuscular injection of the drug. There were no great differences in the amount of the metabolites of diazepam after different kinds of administration. The subjective sedatory effect of diazepam lasted approximately as long as the fast distribution of diazepam from plasma took place. A very highly significant correlation between plasma concentration and subjective sedatory effect of diazepam after a single dose was found.