药物代谢动力学研究(Ⅰ)——硫脒头孢菌素

本文对硫脒头孢菌素在7例健康受试者体内的药物代谢动力学过程,以及合用丙磺舒的影响,进行了初步的分析。 静脉注射后的血药浓度-时间曲线符合开放型二室模型;但肌内注射时可以简化为开放型单室模型。 合用丙磺舒对硫脒头孢菌素药代动力学过程的影响比较复杂。对计算的主要结果进行分析讨论后认为:丙磺舒能够抑制硫脒头孢菌素的经尿排泄,表现在尿药排泄量减少,血药峰浓度及血药浓度-时间曲线下总面积增加。对合用丙磺舒的临床意义也进行了讨论。 与常用头孢菌素的药代动力学特性,进行了讨论比较。     

左旋氧氟沙星对苯妥英钠在家兔的药代动力学影响的研究

目的 :研究左旋氧氟沙星对苯妥英钠血药浓度及药代动力学参数的影响。方法 :应用紫外分光光度法测定家兔喂服左旋氧氟沙星前及10d后单剂量静脉注射苯妥英钠的经 -时血药浓度 ,以“3p87”药代动力学程序拟合药动学参数。结果 :苯妥英钠经 -时血药曲线符合二室开放模型 ,合用左旋氧氟沙星后 ,苯妥英钠血药浓度均有不同程度的降低 ,部分药代动力学参数也有明显的改变。结论 :提示两药合用使苯妥英钠代谢明显加快     

丙磺舒对头孢克罗肠道吸收的影响(英文)

目的:研究不同剂量丙磺舒联用对头孢克罗肠道吸收的影响及其可能机制。方法:(1)药代动力学试验:头孢克罗(100mg/kg)对大鼠静脉给药,分别与不同剂量丙磺舒(0、300、600、900mg/kg)联用,HPLC监测用药后不同时间的血药浓度,DAS软件计算头孢克罗的药代动力学参数。(2)肠道吸收试验:头孢克罗(30μg/mL)分别与不同剂量丙磺舒(0、90、180、270μg/mL)联用,对大鼠在体肠回流给药,给药后不同时间采样,HPLC测定灌流液中头孢克罗浓度的经时变化。结果:(1)头孢克罗静脉给药的血药浓度-时间曲线呈二室开放模型;在试验剂量范围内,随丙磺舒联用剂量增大,头孢克罗的血药浓度呈剂量依赖性增高;AUC与丙磺舒联用剂量呈正相关(r=0.997),而Cl、Vd及V1与丙磺舒联用剂量呈负相关(r=-0.837,-0.817及-0.888)。(2)大鼠在体肠回流实验表明,不同剂量丙磺舒联用对头孢克罗肠道吸收影响的程度不同,当丙磺舒联用剂量达270μg/mL水平时,灌流液内头孢克罗的留存率明显增高。结论:与适量丙磺舒联用,头孢克罗分布容积及血浆清除率降低,血药浓度增高;而与大剂量丙磺舒联用则明显延缓或抑...     

国产氧哌羟苯唑头孢菌素的临床药理研究

氧哌羟苯唑头孢菌素(Cefoperazone)为一第三代头孢菌素。本文报道国产氧哌羟苯唑头孢菌素正常人体内药代动力学研究结果和给药方案的探讨。 在10名健康志愿者中,分别肌注1g,静脉推注1g,静脉滴注1g和2g本品,给药后不同时间留取血、尿标本并记录尿量,用微生物法测定药物浓度。肌注和静注本品的体内药代动力学过程分别符合一房室开放模型和二房室开放模型。     

氯沙坦对兔体内环孢素A药代动力学的影响

目的研究氯沙坦对兔体内环孢素A（CsA）药代动力学的影响。方法采用荧光偏振免疫法测定6只家兔单用及合用氯沙坦后CsA的血药浓度,并对两组动物药代动力学参数进行统计学分析。结果合用氯沙坦后CsA的峰浓度（Cmax）、药时曲线下面积（AUC）显著升高,清除率（CL）及表观分布容积（V）显著降低,其余药代动力学参数无显著性变化。结论氯沙坦可升高CsA的血药浓度,临床上两药合用必须监测CsA的血药浓度,保证治疗安全有效。     

靶向给药系统的多室线性循环药物动力学模型研究

作者建立了靶向给药系统的多室性循环药物代谢动力学模型。导出了血药浓度－－时间和靶药浓度－－时间函数关系式。据此，可由血药浓度－－时间数据求算靶药浓度－－时间曲线，并据后者给出靶器官的药代动力学参数。用肝靶向毫微粒动物实验获得的血药浓度－－时间曲线和肝药浓度－－时间曲线验证了该模型，结果满意。本文还提出用“相对靶向性参数”作为靶向给药系统靶向性定量评价参数，也对模型的特点进行了讨论。     

可乐必妥在健康志愿者及下呼吸道感染病人中的药代动力…

本文对１０名健康志愿者及１２名下呼吸道感染病人进行了多次口服可乐必妥的药代动力学和病人喀痰液浓度的研究。血、尿、痰液标本均采用高效液相色谱法测定，数据由ＳＳＤ程序处理。血药浓度－时间曲线符合二室模型。     

非线性最小二乘法及BP神经网络在血管外给药动力学模拟中的应用

由微分方程推导出血管外给药的一般药动学过程,并通过微分求解得到血药浓度与时间的关系函数,利用非线性最小二乘法拟合原理联立函数对实际药代动力学数据进行模拟,较好的得到血药浓度-时间曲线关系式。同时利用BP神经网络对数据进行模拟,同样得到较好的结果。将最小二乘法拟合与神经网络模拟结果进行t检验,结果无显著性差异。此外对复杂药代动力学过程做了讨论,得出BP神经网络能较好的模拟复杂药代动力学过程的结论。     

头孢硫脒在大鼠生理药动学模型研究

目的 建立头孢硫脒在大鼠的生理药代动力学模型.方法 按照血流限速理论,采用Matlab系统构建生理药代动力学模型程序;模型包括血液、心脏、肺、肾脏、肝脏、肠、胃、脾、胰腺、骨骼肌、皮肤、脂肪和甲状腺等生理相关性组织.生理性模型参数归纳自文献,组织-血液平衡分配系数等药物相关系数由实验测定.结果 大鼠经脉给与头孢硫脒200mg/kg后,模型预测的药物浓度与试验观察值符合良好.结论 建立了头孢硫脒在大鼠的生理药代动力学模型.     

西伐他汀延缓7位中国健康男子环孢素药物代谢

目的：研究西伐他汀对环孢素药物动力学的影响。方法：男性汉族健康志愿者７人随机交叉口服单剂量环孢素１００ｍｇ和同时口服西伐他汀１０ｍｇ后，采用特异性荧光偏振免疫法测定环孢素全知药物浓度。结果：血药浓度－时间曲线拟合表明该药物体内过程符合二室开放模型，合用西伐他汀前后环孢素的主要药代动力学参数，合用西伐他汀前后环孢素的主要药代动力学参数：Ｃｍａｘ（６４６±９４）和（６９８±３４０）μｇ·Ｌ＾－１；Ｔｍ     

3H羟基斑蝥胺的药物代谢动力学研究

将氚标记的羟基斑蝥胺在大鼠体内研究了药物代谢动力学。所得血药浓度-时间数据依一定程序在709电子计算机上拟合曲线,并计算有关参数。结果表明,静脉注射后符合二房室开放型模型,其药代动力学参数为:t1/2α0.067hr,t1/2β2.208hr,V_d(面积)1.237l/kg,V₁0.264l/kg,K_el1.470 hr^-1,清除率0.388l/hr/kg。灌胃后可以单室开放型模型描述,其药代动力学参数为:K_α2.990hr^-1,K_el0.257hr^-1,V_d1.603l/kg,t1/22.693hr,t_max0.90hr,C_max0.745μg/ml,F94.15%。尚将本药以静脉和灌胃两种途径给药后直接观察在大鼠体内的组织分布和在尿粪胆汁中的排泄,结果表明本药分布广,主要经肾排泄,且排泄较快,与药代动力学分析结果相一致。     

齐墩果酸磷酸酯二钠盐的药物动力学与生物利用度研究

采用高效液相色谱法对齐墩果酸磷酸酯二钠盐 (disodiumoleanolicacidphosphate,以下简称为OLANa2 )进行了大鼠体内的药物动力学与生物利用度研究。大鼠静脉注射 3种不同剂量 ( 4 0、5 0、6 0mg/kg)的OLANa2 注射液后 ,其药物动力学行为均符合二室开放模型特征 ,且在实验剂量范围内其药时过程为线性动力学。大鼠灌胃及肝门静脉给药后 ,其药时过程符合单室开放一级吸收模型特征。大鼠经灌胃、肝门静脉、颈静脉交叉给药后 ,灌胃的绝对生物利用度为 2 2 0 3% ,肝门静脉注射的绝对生物利用度为 88 89% ,胃肠道代谢或未吸收部分共为 6 6 9%。     

Pharmacokinetics of cephradine given intravenously with and without probenecid.

1 In the light of questions raised by an earlier oral study (Welling, Dean, Selen, Kendall & Wise, 1979) the influence of probenecid on the pharmacokinetics of intravenously administered cephradine has been investigated. 2 Intravenous administration of cephradine resulted in a bi-exponential curve and the level of antibiotic after 15 min was significantly greater when subjects received probenecid than when they did not. The influence of probenecid on urinary excretion of cephradine was similar to that observed previously. 3 The increase in serum of cephradine due to probenecid could be accounted for by the decrease in the elimination rate of the antibiotic. These results are discussed in the light of other observations.     

Steady-state pharmacokinetics of rufloxacin in elderly patients with lower respiratory tract infections.

The pharmacokinetics of rufloxacin, after repeated doses, was evaluated in 12 elderly patients with lower respiratory tract infections. Patients were given a single loading dose of 400 mg on the first day of treatment and single daily maintenance doses of 200 mg for the next 6-9 days. Serum concentrations of the drug were determined by high-performance liquid chromatography (HPLC) at regular intervals during treatment and fitted to a one-compartment open model for repeated doses. The maximum serum concentration after the first dose was 6.46 +/- 1.06 (mean +/- SEM) micrograms/ml and was reached in 4.3 +/- 0.8 h after the first administration. The elimination half-life was 28.7 +/- 4.1 h. The area under the serum levels-time curve from 0 to 24 h was 103 +/- 14 micrograms/h/ml after the first dose. On the last day of observation it increased to 155 +/- 28 micrograms/h/ml, with a mean extent of accumulation of 2.3 +/- 0.3 times. The elimination half-life was comparable to those in other studies in healthy young subjects, while plasma levels were about 80% higher. These results suggest that in elderly patients elevated drug concentrations may be reached in the serum. Although no untoward reactions related either to the drug concentration in serum or the dose have been noted with rufloxacin, this patient population should nevertheless be monitored carefully for adverse effects.     

Pharmacokinetics of dipyridamole.

Dipyridamole, though originally introduced as a coronary vasodilator, has lately been increasingly investigated in the treatment of thromboembolic diseases because of its inhibitory influence upon blood platelet function. The compound is eliminated from the organism by hepatic biotransformation to the monoglucuronide, which almost exclusively is subjected to biliary and faecal excretion with simultaneous partial enterohepatic circulation taking place. Only minute amounts are excreted through the kidneys. In experiments on four normal human volunteers it was found that the serum concentration curve after intravenous administration of dipyridamole rather closely fits the pharmacokinetics of an open two-compartment model with first order, linear disposition kinetics and elimination taking place from the central compartment. Experiments with oral ingestion of the compound could be described by the use of a corresponding pharmacokinetic model with two consecutive first order input steps, representing the dissolution and absorption processes. The disposition rate constants (beta) were within the range of 0.0051--0.0083 min.-1 corresponding to biological half-lives of 84--145 min. The absorption rate constant was about 0.07 min.-1, and the systemic availability of an oral dose of 100 mg dipyridamole in tablets varied from 37 to 66%.     

Pharmacokinetic modelling of pentoxifylline and lisofylline after oral and intravenous administration in mice

The aim of this study was to develop pharmacokinetic models for pentoxifylline (PTX) and the R(-)-enantiomer of the PTX metabolite 1, lisofylline (LSF), in order to identify some factors influencing the absorption of these compounds from the intestines and to clarify mechanisms involved in their non-linear pharmacokinetics. Serum samples were collected after oral and intravenous administration of PTX and LSF to male CD-1 mice at two different doses. In addition, both compounds under investigation were coadministered with a modulator of drug transporters, verapamil, and an inhibitor of cytochrome P450 (CYP) 3A4, ketoconazole. Pharmacokinetic analysis revealed that a one-compartment model with Michaelis-Menten type absorption and elimination best described the pharmacokinetics of PTX, whereas the LSF concentration-time data were adequately fitted to a two-compartment model with a first-order absorption and Michaelis-Menten type elimination process. Both coadministered compounds significantly decreased the area under the concentration-time curve from 0 to 60 min calculated for PTX and increased the value of this parameter for LSF. The results of this study indirectly suggest that saturation of drug transport across intestinal cells and elimination from the central compartment may be responsible for the non-linear pharmacokinetics of PTX, whereas in the case of LSF, the dose dependency in the pharmacokinetics is solely related to the elimination from the central compartment. It seems that the observed changes in PTX and LSF concentrations after coadministration with verapamil and ketoconazole may be clinically significant, especially after chronic treatment, however further studies are necessary to assess the importance of these interactions in humans.     

Saturable Processes Affecting Renal Clearance of Cefixime in Dogs

The pharmacokinetics of cefixime, a new orally active cephalosporin, was studied after an intravenous dose of 50 mg/kg to four beagle dogs. Cefixime was shown to exhibit concentration dependent serum protein binding and saturable tubular reabsorption. The drug was excreted mainly in the urine, the net result of glomerular filtration and saturable tubular reabsorption. The experimental results were analyzed by model independent pharmacokinetic equations and with theoretical models describing renal clearance. Modification of the models, based on observed data, was proposed. The experimental methods employed and the pharmacokinetic approach offered in this study can be applied to drugs that exhibit concentration dependent protein binding and saturable renal elimination processes.     

Pharmacokinetics and tissue distribution of piperine in animals after i.v. bolus administration

A reverse phase HPLC method to determine piperine, a pungent constituent of black pepper, in rabbit serum and various tissues of the rat was developed. A pharmacokinetic study was performed in rabbits and tissue distribution studies were carried out in rats. High reproducibility was achieved in quantitative analysis over the concentration range of 0.2-20 micrograms/ml serum. After bolus intravenous administration of piperine at a dose of 10 mg/kg, the serum concentration--time curve fitted the two-compartment open model. The tissue distribution pattern of piperine in rats also supports the two-compartment open model.     

Probenecid affects the pharmacokinetics of ofloxacin in healthy volunteers

OBJECTIVE: The aim of this randomised, double-blind, crossover study was to evaluate the effect of single-dose probenecid on the pharmacokinetics of ofloxacin in eight healthy male volunteers. METHODS: After an overnight fast, and according to a randomised sequence, each volunteer received either single oral ofloxacin 200mg (Hoechst Marion Roussel Ltd., Mumbai, India) or both ofloxacin (1 x 200mg) and probenecid (1 x 500mg) [Geno Pharmaceutical Ltd., Mumbai, India]. Blood samples were collected at regular intervals until 24 hours. Serum concentration versus time profiles for ofloxacin were generated and pharmacokinetic parameters were calculated by noncompartmental model analysis. Results: Elimination half-life, mean residence time and area under the curve were significantly increased (4.86 vs 5.26h; 7.23 vs 7.95h; 10.28 vs 11.9 mg/L . h) [p < 0.01], whereas the total clearance was decreased (19.66 vs 16.95 L/h) [p < 0.01] in the presence of probenecid. Other pharmacokinetic parameters were not significantly affected by coadministration of probenecid. CONCLUSION: Concomitant administration of probenecid with ofloxacin may result in a decreased elimination half-life and consequently increased bioavailability of ofloxacin. Probenecid may be co-prescribed with ofloxacin; patients taking this combination should be closely monitored and dosage reduction should be considered if warranted in high-risk patients.     

Pharmacokinetics of amosulalol, an alpha, beta-adrenoceptor blocker, in rats, dogs and monkeys

The pharmacokinetics of an alpha, beta-adrenoceptor blocker, amosulalol hydrochloride, were studied after i.v. and oral administration to rats, dogs and monkeys. After an i.v. dose (1 mg/kg), the plasma concentration-time curve fitted a two-compartment open model with terminal half-lives of 2.5 h in rats, 2.1 h in dogs and 1.8 h in monkeys. The order of plasma clearances for amosulalol was: rats greater than dogs greater than monkeys. After oral administration, the maximum plasma concentration was obtained at 0.5-1 h in rats (10-100 mg/kg) and dogs (3-30 mg/kg), and at 1.7-2.7 h in monkeys (3-10 mg/kg). A linear relationship between the area under the plasma concentration-time curve and dose administered was obtained for all three species. The systemic availabilities of the drug in rats, dogs and monkeys were 22-31%, 51-59% and 57-66%, respectively. After repeated oral administration (10 mg/kg) to dogs for 15 days, the pharmacokinetic parameters did not differ significantly from those on the first day.