蝙蝠葛苏林碱在犬体内药动学-药效学结合模型研究

目的 :研究蝙蝠葛苏林碱在beagle犬体内的药动学与药效学之间的关系。 方法 :4只beagle犬给予蝙蝠葛苏林碱 6mg·kg-1静脉注射后 ,分时取血 ,同时通过生理记录仪观察犬心电、血压及血流动力学的变化。采用反相高效液相色谱法测定血浆中蝙蝠葛苏林碱的浓度。结果 :蝙蝠葛苏林碱在犬体内动力学行为符合二房室开放模型 ,对犬药效学影响峰值为 10～ 15min ,皆明显滞后于血药浓度峰值。结论 :通过在beagle犬体内建立的蝙蝠葛苏林碱药动学 药效学 (PK PD)结合模型 ,可以成功预测蝙蝠葛苏林碱的血药浓度及其药理效应。     

蝙蝠葛苏林碱和蝙蝠葛碱在犬体内的药动学-药效学模型

目的：研究蝙蝠葛苏林碱和蝙蝠葛碱在beagle犬体内的药动学-药效学结合模型,并比较两种药物对其心电、血压和血流动力学的作用。方法：利用反相高效液相色谱法测定其血药浓度,生理记录仪观察药理效应,并计算药动学和药动学-药效学结合模型参数．结果：血药浓度-时间数据符合二房室开放模型．药效与效应室药物浓度之间的关系符合sigmoid-Emax模型．主要药动学和药动学-药效学结合模型参数在两种药物间差异无显著性．结论：蝙蝠葛苏林碱和蝙蝠葛碱在beagle犬体内的处置规律和对心血管系统的抑制作用基本-致。     

蝙蝠葛碱在犬体内的药代动力学和药效动力学研究

目的　应用药动学药效学结合模型方法研究蝙蝠葛碱在犬体内的药代动力学和药效动力学之间的关系。方法　4只beagle犬给蝙蝠葛碱6mg·kg-1静脉注射后,分时取血及行心电、血压及血流动力学变化观察。采用反相高效液相紫外法测定血浆中蝙蝠葛碱的浓度。结果　蝙蝠葛碱主要药动学参数T1 /2α,T1 /2β,Vd,AUC分别为(0 049±0 016)h,(2 .7±0. 6)h, (15. 8±3 5)L·kg-1和(1. 48±0. 17)mg·h·L-1。对Q Tc的最大延长率为( 25 5±9 4 )%;SBP,DBP,±(dp/dt)max的最大抑制率分别为( 23 .0±4. 9 )%,(21 .9±5. 9)%, ( 42. 8±6 .6 )%和( 39 .0±17 .1 )%。药理效应滞后于血药浓度10 ~15min。药理效应与效应室浓度之间的关系符合sigmoid Emax模型。结论　建立了蝙蝠葛碱在犬体内血药浓度、时间、药物效应三者之间的关系。     

上消化道出血儿童法莫替丁的药动学和药效学考察

目的:研究上消化道出血儿童法莫替丁的药动学和药效学。方法:采用高效液相色谱法测定血清中法莫替丁浓度,以DAS药动学程序计算药动学参数,24h动态胃内pH监测来评价药效。结果:上消化道出血儿童首次静脉滴注法莫替丁(0.9mg.kg-1)后,体内过程符合一室模型。t1/2为(1.7±0.7)h,Vd为(2.0±1.0)L.kg-1,CL为(0.5±0.3)L.h-1.kg-1;胃内pH>4的持续时间约为6h。结论:静脉滴注法莫替丁(0.9mg.kg-1)可显著抑制胃酸分泌,抑酸作用滞后于血药浓度。儿童不同个体间的药动学差异较大。     

高蛋白饮食对犬体内左氧氟沙星药动学的影响研究

目的:研究高蛋白饮食对犬体内左氧氟沙星药动学的影响。方法:将6只犬随机均分为空腹组和高蛋白饮食组,高蛋白饮食组犬进食高蛋白饮食每只150g,2组犬分别灌服左氧氟沙星10mg/kg。采用高效液相色谱法检测给药后0.5、1、2、4、8、12、24、48h各组犬体内左氧氟沙星的血药浓度,2周后进行交叉实验,3p97软件计算药动学参数并进行比较。结果:2组犬体内左氧氟沙星的药动学过程均符合二室模型;空腹组和高蛋白饮食组犬体内左氧氟沙星的药动学参数分别为t1/2β:(11.07±8.46)、(21.65±4.65)h,tmax:(3.42±0.41)、(1.53±0.34)h,cmax:(2.71±0.60)、(2.22±0.22)μg/ml,AUC0-48h:(36.51±8.66)、(29.78±4.26)μg·h/ml;除tmax参数组间有显著性差异(P<0.01)外,其余参数均无显著性差异(P>0.05)。结论:高蛋白饮食可使左氧氟沙星tmax减小,促进其吸收。     

苦参素注射液在犬体内的药动学过程

目的:建立用HPLC法测定血浆中苦参素浓度的方法,考察苦参素注射液犬体内的药动学过程.方法:以氯仿-正丁醇(98:2)为提取溶剂处理血样.6条beagle犬iv苦参素注射液,测各时间点血药浓度,PAPP 2.0程序处理数据.结果:苦参素注射液犬体内的各个重要药动学参数如下:α为(0.053±0.007)μg·min-1,β为(0.008 3±0.001 0)μg·min-1,t1/2β为(84.1±4.3)min,k10为(0.025±0.003)μg·min-1,k12为(0.018 8±0.002 0)μg·min-1,k21为(0.018±0.003)μg·min-1,AUC为(85.9±11.3)mg·h·L-1.结论:本法提取回收率较高,拟合结果表明苦参素体内分布属于二室开放模型.     

盐酸莫西沙星片剂的血药浓度及药动学分析

目的 分析盐酸莫西沙星在人体内的血药浓度及药动学.方法 10名志愿受试者单剂量口服莫西沙星400mg后,采用固相萃取-高效液相色谱方法测定盐酸莫西沙星的血药浓度及药动学参数,用DAS2.0软件自动拟合处理,计算药动学参数.结果 莫西沙星的药动参数:t1/2α=(5.26±0.20)h;t1/2 β=(7.80±0.50)h;AUC(0～t)=(111.8±10.3)μg/ (mL·h);tmax=(3.13±0.32)h;Cmax=(13.5±0.42) μg/ mL;莫两沙星在体内的药-时曲线符合二室开放模型,在体内消除半衰期为12h,生物利用度约为95.4％.结论 该方法操作简单、准确可靠,可用于莫西沙星的临床药动学研究及临床特殊人群的血药浓度测定.     

美托洛尔光学异构体在犬体内的药动学-药效学结合模型

用麻醉犬研究美托洛尔(Met)光学异构体药动学—药效学结合模型。结果表明,ig(+)-Met或(-)-Met后,其药动学符合二室模型,药动学参数V_d/F,CLs/F和AUC在两种Met之间有显著性差异。(+)-Met和(-)-Met的效应和血药浓度关系呈逆时针滞后环。引入效应室理论后,药效和效应室浓度之间的关系符合Sigmoid-E_max模型。应用CAPP软件进行模型拟合,血药浓度的预测值和药效的预测值皆与其实测值较为接近。(+)-Met抑制V_max,dp/dt_max及HR效应的Ce₅₀分别是(-)-Met的3.7,6.8,6.3倍,证实(-)-Met对犬心脏的抑制作用强于(+)-Met。     

地西泮亚微乳注射液大鼠体内药动学

目的:研究地西泮亚微乳注射液在大鼠体内药动学特征.方法:大鼠股静脉注射地西泮亚微乳注射液(4 mg·kg-1),采用HPLC法测定不同时间点大鼠血浆中的药物浓度,并用3P87药动学程序对血药浓度进行处理.结果:地西泮可与血浆中的其他成分较好地分离,在0.05～5 mg·L-1的血药浓度范围内呈良好的线性关系.地西泮亚微乳注射液和地西泮注射液2种制剂大鼠静脉给药后体内药动学符合三室模型,主要药动学参数t1/2β,AUC0～∞,MRT和Vc分别为:(10.97±1.89)和(5.72±1.24)h,(6.10±1.25)和(6.24±1.80)mg·L-1·h,(15.67±1.48)和(9.98±1.31)h,(0.34±0.03)和(0.10±0.01)L·kg-1;2种制剂的t1/2β,MRT和Vc均存在统计学差异(P＜0.01).结论:地西泮亚微乳注射液可在一定程度上延长药物体内循环时间.     

苯扎贝特缓释片在犬体内的药动学

目的:研究单剂量和多剂量口服苯扎贝特缓释片在Beagle犬体内的药动学特征。方法:4只Beagle犬单剂量和多剂量口服苯扎贝特缓释片后,不同时间点采集血样。采用高效液相色谱法测定其血药浓度,应用Topfit2.0软件计算其主要药动学参数。结果:苯扎贝特缓释片给药后主要药动学参数如下:单剂量Cmax为(19.8±6.7)mg.L-1,tmax为(2.3±0.8)h,AUC0-τ为(80.0±35.8)mg.h.L-1,t1/2为(8.5±1.5)h;多剂量Cmax为(21.5±6.0)mg.L-1,tmax为(2.8±1.1)h,AUC0-τ为(114.3±63.0)mg.h.L-1,t1/2为(8.8±4.5)h。结论:本法灵敏度高,简便,分析速度快,专属性强,可用于犬血浆中苯扎贝特的测定。苯扎贝特缓释片口服给药符合二房室模型,多次给药无明显蓄积现象。     

Pharmacokinetic-pharmacodynamic modeling of diltiazem in spontaneously hypertensive rats: a microdialysis study

INTRODUCTION: The aim of the present work was to study the applicability of a modified E(max) pharmacodynamic model for the pharmacokinetic-pharmacodynamic (PK-PD) modeling of diltiazem in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats. METHODS: A "shunt" microdialysis probe was inserted in a carotid artery of anaesthetized SHR and WKY rats for simultaneous determination of unbound plasma concentrations of diltiazem and their effects on mean arterial pressure (MAP) and heart rate (HR) after the intravenous application of 1 and 3 mg kg(-1) of the drug. Correlation between diltiazem plasma levels and their cardiovascular effects was established by fitting the data to a conventional and modified E(max) model. RESULTS: Volume of distribution and clearance of diltiazem was greater in SHR than in WKY animals. A proportional increase of area under curve with dose increment was observed in WKY animals but not in SHR. A good correlation between plasma unbound concentrations of diltiazem and their hypotensive and chronotropic effects was found in both experimental groups using both PK-PD models. The application of the modified E(max) model for PK-PD modeling of diltiazem allowed a more accurate and precise estimation of PK-PD parameters than the E(max) equation do. Chronotropic effect of 3 mg kg(-1) diltiazem was lower in SHR compared to WKY animals. Initial sensitivity (S(0)) to diltiazem chronotropic effect was greater in SHR with regards to WKY animals after administration of 1 mg kg(-1). S(0) to diltiazem hypotensive effect was greater in SHR with regards to WKY animals after administration of both doses of diltiazem. DISCUSSION: Microdialysis sampling is a useful technique for the pharmacokinetic study and pharmacokinetic-pharmacodynamic (PK-PD) modeling of diltiazem. The modified E(max) model allows an accurate estimation of drug sensitivity in conditions when maximal pharmacological response can not be attained. Genetic hypertension induced changes in the pharmacokinetic and PK-PD behavior of diltiazem suggesting that SHR is an interesting animal model for pre-clinical evaluation of calcium channel blockers.     

Disposition of pentopril, a new orally active angiotensin-converting enzyme inhibitor, and its active metabolite in rats

The disposition characteristics of pentopril (the ethyl ester) and its active carboxylic acid metabolite (CGS 13934) were determined in conscious rats after separate intravenous administrations of both compounds. The relationship between plasma concentration and pharmacological effect was also evaluated. The extent of apparent bioavailability of the active metabolite was determined after oral administration of pentopril. Pharmacokinetic parameters were calculated from the plasma concentration-time data for both the parent drug and its active metabolite after their separate intravenous administrations using a one-compartment model for the drug and a two-compartment model for the metabolite. The elimination half-life for the drug was approximately 1 min. The elimination half-life for the metabolite was 13 min (SD, +/- 3.5, n = 4) after its direct intravenous administration, but increased to an apparent half-life of 20 min (SD +/- 5, n = 5) when formed in vivo as a metabolite. Comparison of the formation rate of the metabolite and the elimination rate of the parent drug indicated that the parent drug was rapidly and completely hydrolyzed to the acid metabolite as soon as it reached the systemic circulation. No parent drug was detected in plasma after its oral administration. The apparent bioavailability of the acid metabolite was 66% after oral drug administration. A close relation between inhibition of pressor response to angiotensin I (AI) and plasma concentration of the active metabolite was observed when plotted against time after drug or metabolite administration. A Michaelis-Menten function correlated (multiple r2:0.995) well between effect and plasma metabolite concentration with mean concentration for 50% of maximum inhibition, IC50, of 3.6 X 10(-7) M (0.11 microgram/mL).     

家兔静脉注射与口服左氧氟沙星后血浆和眼房水药动学比较

目的:比较家兔静脉注射与口服左氧氟沙星后血浆和眼房水药动学.方法:选取54只家兔,分别静脉注射或口服左氧氟沙星24 mg/kg,高效液相色谱法测定血浆和眼房水药物浓度,3p97软件计算药动学参数.结果:静脉注射与口服血浆中左氧氟沙星t1/2分别为(1.42±0.29)h和(2.99 ±0.20)h(P＜0.01);AUC(0-t)分别为(42.56±3.71) μg·h·mL-1和(33.48±2.98)μg·h·mL-1(P＜0.01).房水中左氧氟沙星t1/2分别为(2.53±0.65)h和(2.68±0.70)h;tmax分别为(0.50±0.00)h和(0.67±0.24)h(P＜0.05);Cmax分别为(4.93±0.83)μg/mL和(1.59±0.38) μg/mL(P＜0.01).结论:左氧氟沙星口服给药可在血浆和房水中达较高药物浓度,但静脉注射更为明显,二者有明显差别.     

Pharmacokinetics and pharmacological effects of neostigmine in man.

1 The pharmacokinetics of neostigmine was studied in six patients during the reversal of neuromuscular block induced by tubocurarine chloride. The effect of the drug on neuromuscular function was simultaneously assessed by electromyography. 2 Neostigmine was rapidly eliminated from plasma after intravenous administration. The decline in the plasma concentration of the drug was invariably resolved into two exponential components. The fast disposition (distribution) half-life of the drug was invariably less than 1 min; the slow disposition (elimination) half-life ranged from 15.4--31.7 min. 3 Neostigmine usually increased the amplitude of the compound muscle action potential and diminished electromyographic decrement within 2 min of intravenous injection. The pharmacological effect of neostigmine was usually maximal between 7 and 15 min. There was an inverse relationship between the plasma concentration of the drug and the facilitation of neuromuscular transmission. 4 Red cell acetylcholinesterase activity was almost completely inhibited within 2--3 min of intravenous injection of neostigmine. Enzyme activity recovered to approximately 28% of control values by 30 min and to 55% by 60 min.     

生脉注射液中人参皂苷Rc在心绞痛患者体内的PK-PD相关性

目的 评价生脉注射液中人参皂苷Rc在心绞痛患者体内的药代动力学-药效动力学（PK-PD）相关性。方法 10名稳定性心绞痛受试者连续静脉滴注生脉注射液14 d,分别于给药后不同时间点采集血浆样品,采用液相色谱-串联质谱（LC-MS）法测定血浆中人参皂苷Rc的血药浓度,绘制药-时曲线,进行非房室模型拟合并计算PK参数;以受试者的收缩压（SBP）、舒张压（DBP）及心率（HR）作为药效指标,进行PK-PD结合模型的拟合,计算PK-PD参数。结果 人参皂苷Rc在心绞痛受试者体内的PK符合二室模型,其降压及加快HR的效应滞后于血药浓度,不与血药浓度直接相关;效应室浓度与药效之间具有良好的相关性,血压和HR的效应模型分别符合Inhibitory Effect Sigmoid I_max和Sigmoid E_max模型。结论 成功建立了生脉注射液中人参皂苷Rc在心绞痛患者体内的PK-PD结合模型,可有效地用于预测其血药浓度和效应,评价药效物质基础。     

HPLC法测定蝙蝠葛碱与大鼠和人血浆蛋白的结合率

目的:建立测定蝙蝠葛碱的高效液相色谱(HPLC)法,并研究蝙蝠葛碱与大鼠和人血浆蛋白的结合率。方法:采用平衡透析法,HPLC法测定蝙蝠葛碱的浓度,计算蝙蝠葛碱大鼠及人血浆蛋白结合率。结果:透析外液中的蝙蝠葛碱检测浓度在0.24～15.10μg.mL-1范围内与其峰面积积分值呈良好线性关系;大鼠血浆中的蝙蝠葛碱检测浓度在0.24～15.10μg.mL-1范围内与其峰面积积分值呈良好线性关系;人血浆中的蝙蝠葛碱检测浓度在0.24～15.10μg.mL-1范围内与其峰面积积分值呈良好线性关系。蝙蝠葛碱在高、中、低浓度下,其大鼠血浆蛋白结合率分别为(69.63±1.30)%、(68.64±1.10)%、(72.54±0.50)%,人血浆蛋白结合率分别为(82.1±1.00)%、(84.96±0.70)%、(78.79±0.60)%。结论:HPLC法用于蝙蝠葛碱生物样品测定具有简便、灵敏与选择性高的特点;蝙蝠葛碱具有较强的血浆蛋白结合率,且大鼠和人血浆蛋白结合率具有种属差异性,人血浆蛋白结合率高于大鼠血浆蛋白结合率(P<0.05)。     

A signal transduction pharmacodynamic model of the kinetics of the parasympathomimetic activity of low-dose scopolamine and atropine in rats

We used a novel pharmacokinetic-pharmacodynamic (PK-PD) approach that had been applied for signal transduction kinetics to investigate the kinetics of the parasympathomimetic effect of scopolamine and atropine in rats. The parasympathetic tone was assessed by continuous measurement of the power of the high frequency band (HF) of electrocardiogram (ECG) R-R intervals obtained by power spectral analysis (PSA) of heart rate variability (HRV). To overcome the inherent noise of the HRV-HF data and to quantitatively identify temporal changes in the autonomic tone, a new approach of stepwise regression of the cumulative HF data was applied. The elevation of the parasympathetic tone occurred after a significant lag time (>70 min) following scopolamine administrations [0.25 and 0.5 mg/kg intravenous (iv) bolus or infusion over 100 min], followed by a gradual return to the baseline levels. A similar lag time in parasympathetic stimulation was observed following iv bolus administration of atropine (0.1 mg/kg). The plasma drug concentration versus time data were linked to the response versus time data using a signal transduction pharmacodynamic model that was fitted simultaneously to all four experimental data sets. This PK-PD model resolved the significant discrepancy between the concentration versus time and the response versus time patterns and successfully described the kinetics of the parasympathetic stimulation obtained for different drugs and different rates of administration. This work paves the way for further PK-PD preclinical investigations in this field.     

Pharmacokinetic–pharmacodynamic modelling of intravenous and oral topiramate and its effect on phonemic fluency in adult healthy volunteers

Aims

The aim was to develop a quantitative approach that characterizes the magnitude of and variability in phonemic generative fluency scores as measured by the Controlled Oral Word Association (COWA) test in healthy volunteers after administration of an oral and a novel intravenous (IV) formulation of topiramate (TPM).

Methods

Nonlinear mixed-effects modelling was used to describe the plasma TPM concentrations resulting from oral or IV administration. A pharmacokinetic–pharmacodynamic (PK-PD) model was developed sequentially to characterize the effect of TPM concentrations on COWA with different distributional assumptions.

Results

Topiramate was rapidly absorbed, with a median time to maximal concentration of 1 h and an oral bioavailability of ∼100%. Baseline COWA score increased by an average of 12% after the third administration on drug-free sessions. An exponential model described the decline of COWA scores, which decreased by 14.5% for each 1 mg l⁻¹ increase in TPM concentration. The COWA scores were described equally well by both continuous normal and Poisson distributions.

Conclusions

This analysis quantified the effect of TPM exposure on generative verbal fluency as measured by COWA. Repetitive administration of COWA resulted in a better performance, possibly due to a learning effect. The model predicts a 27% reduction in the COWA score at the average observed maximal plasma concentration after a 100 mg dose of TPM. The single-dose administration of relatively low TPM doses and narrow range of resultant concentrations in our study were limitations to investigating the PK-PD relationship at higher TPM exposures. Hence, the findings may not be readily generalized to the broader patient population.