异丙酚在人肝微粒体中酶促动力学研究

目的 研究异丙酚在人肝微粒体中的代谢。方法 采用高效液相方法测定孵育液中异丙酚的浓度。研究异丙酚的酶促动力学,推导出药物米氏常数(Km)和最大反应速度(Vmax);并计算体外酶对药物的清除率(CLint)。同时观察不同种类的CYP酶特异性抑制剂对异丙酚代谢的影响。结果 异丙酚在人肝微粒体中Km和Vmax分别为777.43μuM和172.413μM?h ?1?mg ?1?protein,Clint为0.22h?1?mg?1?protein。CYP2B6特异性抑制剂氯吡格雷能够显著抑制异丙酚的代谢,而CYP2C9和CYP2C19特异性抑制剂对异丙酚代谢无显著影响CYP2B6抑制剂能够减少异丙酚的代谢。结论 CYP2B6主要参与异丙酚的代谢, CYP2B6酶抑制剂可能会抑制异丙酚的代谢,造成药物药效或毒性的增加。     

microRNA介导低氧对药物代谢酶和转运体的调控

低氧条件下机体的循环系统、神经系统、内分泌系统等的功能发生显著改变,这些变化影响药物在体内的吸收、分布、代谢和排泄.药物代谢酶和转运体是影响药物代谢的主要因素,微小RNA(microRNA,miRNA)除调控与药物代谢相关的基因如缺氧诱导因子、炎症因子、核受体等,还可直接作用于药物代谢酶和转运体,影响药物的体内代谢.本...     

航天失重条件下药动学研究进展

目的近年来我国载人航天事业发展迅速,载人航天飞行实践次数逐渐增加,极大地推动了航天医学的发展。失重是航天员飞行过程中无法摆脱的不利因素,可以引起机体广泛的生理变化,如体液头向分布、血容量变化、胃肠道功能紊乱等,这些改变或可引起药物在机体内的药物动力学变化,进而影响药物的疗效或产生毒性。目前美国航天局的航天用药仍以地面用药规律为指导,这或会导致航天员用药不安全问题。国内外微重力条件下药动学的研究较为少见,且由于实际飞行次数的限制,相关研究大多通过地面模拟实验来实现。方法结合国内外失重药物动力学的研究进展以及本课题组的相关研究,围绕吸收、分布、代谢、排泄四个过程进行综述。结果与结论总结了失重条件下药动学过程的改变规律,以期为载人航天中的药物应用提供更多基础知识和实验数据。     

食物对药物吸收代谢的影响

药物在机体内将受到各种因素的影响 ,其中饮食是不可忽视的影响因素 ,特别是口服药物进入机体后 ,可能首先在消化道与食物发生各种物理、化学反应 ,改变药物吸收、分布、代谢和排泄 ,从而影响药物治疗作用。食物主要影响药物的吸收和代谢两个环节［１］,笔者就食物对药物吸收和代谢两方面的影响作一综述 ,以期为临床合理用药提供参考。１食物对药物吸收的影响［２～５］１．１食物与药物直接理化作用食物与药物发生理化作用从而影响药物的吸收 ,如牛奶或其它乳制品中的钙离子与四环素形成络合物 ,减少四环素的吸收 ;茶叶水中的鞣酸与铁制剂…     

食物对药物吸收代谢的影响

药物在机体内将受到各种因素的影响,其中饮食是不可忽视的影响因素,特别是口服药物进入机体后,可能首先在消化道与食物发生各种物理、化学反应,改变药物吸收、分布、代谢和排泄,从而影响药物治疗作用。食物主要影响药物的吸收和代谢两个环节[1],笔者就食物对药物吸收和代谢两方面的影响作一综述,以期为临床合理用药提供参考。     

抗菌药的药代动力学与肝脏疾病

肝脏疾病对药物代谢动力学有难以预料的影响,而人们对抗菌药物在这方面却很少有详细的研究;肝病患者使用抗菌药的总原则也是从其它药物借鉴的。肝病患者应用药物时出现较多副作用的机理并不完全清楚。例如氨基糖苷类抗生素,虽然几乎完全从肾脏排泄,但其肾毒性似乎可通过肝脏疾病而被加重。肝病能通过多种途径影响药物代谢,如改变肝廓清率,降低肝代谢能力,或由于门脉高压绕过肝脏,减少血清中与蛋白结合的药物浓度,改变药物与蛋白的亲和力以及改变药物自胃肠道的吸收等。一般说来,肝脏代谢药物的能力相当强,只是在严重肝病时这种能力才受影响,但也有报道急性肝     

浅谈老年人的合理用药问题

由于老年人免疫能力降低，其生理变化使药物吸收、分布、蛋白结合、代谢和排泄等体内过程发生改变，用药品种与数量多影响药物效应与临床疗效，现浅谈老年人的合理用药。一、由于老年人胃蠕动减慢，延迟药物到达小肠的时间，如狄高辛、安定等，使半衰期推迟；在小肠远端吸...     

羧酸酯酶单核苷酸多态性与个体化药物治疗的研究进展

人类羧酸酯酶(carboxylesterases,CESs)属于丝氨酸酯酶超家族,在人体中主要包含羧酸酯酶1(CES1)和2(CES2)2种亚型。CES负责多种药物的代谢,如部分血小板凝集抑制剂、精神兴奋剂、抗肿瘤药等,由于CES的单核苷酸多态性(SNP)在人类基因组中广泛存在,其对药物代谢酶基因的表达和(或)酶活性的高低有着重要影响,从而最终影响着药物在体内的代谢过程。本文综述了CES1和CES2相关SNP所致酶活性的改变,以及由于其多态性导致代谢药物体内过程改变的相关药物基因组学研究,以期为临床治疗和研究提供参考。     

全胃肠外营养同时输注对药物体内药动学/药效学的影响及相关不良事件

全胃肠外营养(TPN)同时输注对药物体内药动学/药效学产生影响。在药动学方面,一是TPN通过影响代谢酶功能和活性,进而影响药物在体内的代谢;二是TPN具有高渗透性,同时输注可影响药物在体内的分布。在药效学方面,TPN中的脂肪乳剂可与血浆蛋白竞争性结合,增加某些药物(如丙戊酸钠)的游离浓度;TPN中脂肪乳剂富含维生素K1,可拮抗华法林的抗凝作用。另外,TPN的输注可引起诸多不良反应,如肝损伤、胆汁淤积、肠功能屏障的改变、静脉栓塞及导管相关性感染。因此,TPN同时输注将影响药物在体内的药动学和药效学特性及临床用药安全,对应用TPN的患者应严密监护。     

大量输血对严重失血患者凝血功能和电解质平衡的影响

<正>大量输血作为常用的支持性和代偿性疗法,是临床上维持血容量和血压、防止休克的重要手段,可迅速纠正失血过多和严重贫血,在失血性手术患者的救治中得到了越来越广泛的应用。大量输注血液时一般为库存血,而库存血在保存的过程中会发生许多代谢改变。当大量库存血输注给危重或严重创伤等严重失血患者时,可引发诸多不良反应,如凝血因子的稀释、血小板减少,甚至出现凝血功能障碍等[1],同时由于代谢的改变,亦可影响其     

The pharmacokinetics of propofol in laboratory animals.

1. The pharmacokinetics of propofol in an emulsion formulation ('Diprivan') have been studied after single bolus doses to rats, dogs, rabbits and pigs, and after single and multiple infusions to dogs. Venous blood propofol concentrations were determined by h.p.l.c. with u.v. or fluorescence detection. Curve fitting was performed using ELSFIT. 2. The distribution of propofol in blood and its plasma protein binding have been studied in rat, dog, rabbit and man. Protein binding was high (96-98%), and in most species propofol showed appreciable association with the formed elements of blood. 3. Where an adequate sampling period was employed the pharmacokinetics of propofol were best described by a three-compartment open 'mammillary' model. Propofol was distributed into a large initial volume (1-21/kg) and extensively redistributed (Vss = 2-10 x body weight) in all species. Clearance of propofol by all species was rapid, ranging from about 30-80 ml/kg per min in rats, dogs and pigs to about 340 ml/kg per min in rabbits.     

A review of the effects of chronic exercise and physical fitness level on resting pharmacokinetics

Pharmacological intervention in cooperation with physical activity is currently being used in the prevention and treatment of diseases like cardiovascular disease and obesity. Physical activity, both acute and chronic, can cause changes in physiology that can alter the observed pharmacokinetics of drugs. OBJECTIVE: The purpose of this paper is to focus on how chronic exercise can change pharmacokinetics. RESULTS: Chronic exercise can affect drug absorption by the increase in collateral blood flow and absorption may also be affected by changes in gastrointestinal transit times. Chronic exercise may affect volume of distribution of drugs by the increases in lean body mass, decreased fat mass, increased plasma protein and increased plasma volume that occurs with physical conditioning. Changes in hepatic clearance of drugs may explain the differences in systemic clearance seen when comparing physically trained subjects to sedentary ones. Some studies have shown that hepatic enzymes are increased with training but other studies have found no change or lower activities. Finally, renal elimination of drugs may be altered by changes in protein binding but there is little evidence that renal elimination of drugs changes with long-term exercise. CONCLUSION: Therefore, changes in pharmacokinetics associated with chronic exercise can differ from those during acute exercise and in sedentary subjects. The differences between the physically active and sedentary individuals may require individualization of dosing regimens. It should be noted that there are no standardized protocols to evaluate the influence of exercise on drug disposition.     

The pharmacokinetics of propofol in laboratory animals

1. The pharmacokinetics of propofol in an emulsion formulation (‘Diprivan’) have been studied after single bolus doses to rats, dogs, rabbits and pigs, and after single and multiple infusions to dogs. Venous blood propofol concentrations were determined by h.p.l.c. with u.v. or fluorescence detection. Curve fitting was performed using ELSFIT.

2. The distribution of propofol in blood and its plasma protein binding have been studied in rat, dog, rabbit and man. Protein binding was high (96-98%), and in most species propofol showed appreciable association with the formed elements of blood.

3. Where an adequate sampling period was employed the pharmacokinetics of propofol were best described by a three-compartment open ‘mammillary’ model. Propofol was distributed into a large initial volume (1-21/kg) and extensively redistributed (V_ss=2-10 x body weight) in all species. Clearance of propofol by all species was rapid, ranging from about 30-80ml/kg per min in rats, dogs and pigs to about 340ml/kg per min in rabbits.     

Protein binding of drugs in plasma,interstitial fluid and tissues: Effect on pharmacokinetics

Summary Drug binding in the interstitial fluid as well as in the plasma must be taken into account when considering the pharmacokinetics of drugs which are highly bound to plasma proteins and have a relatively small apparent volume of distribution (V). The half-life and apparent volume of distribution of such a drug can be affected significantly by changes in the extent of binding of the drug in both the plasma and the interstitial fluid. An alteration in the fraction of drug in the tissues which is unbound will primarily affect the pharmacokinetics of drugs which have a relatively large apparent volume of distribution. The effect of changes in the plasma free fraction of drug (f_P) on tissue binding can be deduced from a plot of f_P versus V, but not from a plot of f_P versus .     

Evidence of Different Propofol Pharmacokinetics under Short and Prolonged Infusion Times in Rabbits

Propofol is an anaesthetic widely used in both human beings and animals. However, the characterization of propofol pharmacokinetics (PK) is not well understood when long‐term infusions are used. The main objective of this study was to explore the PK behaviour of propofol in a rabbit model during short and prolonged propofol infusions and to develop an internally validated PK model, for propofol dose individualization in the rabbit for future use. Population 1 (P1) was constituted by seven New Zealand rabbits and was used to characterize the PK profile of propofol at short infusions. Animals were anaesthetized with a bolus of 20 mg/kg, followed by an infusion rate of 50 mg/kg/hr of propofol at 1%, which was then maintained for 30 min. A second rabbit population (P2, n = 7) was sedated according to reflexes responses and Index of Consciousness values, for 20 consecutive hours using propofol 2% aiming at characterizing propofol behaviour at long‐term infusions. Clinical data and blood samples were collected at specific time‐points in both populations. Propofol plasma concentrations were determined by gas chromatography/ion trap mass spectrometry. The NONMEM VII software was used to evaluate the relationships between dose and plasma concentrations. A linear two‐compartment model with different central compartment volume and plasma clearance (separately modelled in the two populations) was the one that best described propofol concentrations. The time course of propofol plasma concentrations was well characterized by the PK model developed, which simultaneously accounts for propofol short‐ and long‐term infusions and can be used to optimize future PK studies in rabbits.     

The effect of respiratory disorders on clinical pharmacokinetic variables

Respiratory disorders induce several pathophysiological changes involving gas exchange and acid-base balance, regional haemodynamics, and alterations of the alveolocapillary membrane. The consequences for the absorption, distribution and elimination of drugs are evaluated. Drug absorption after inhalation is not significantly impaired in patients. With drugs administered by this route, an average of 10% of the dose reaches the lungs. It is not completely clear whether changes in pulmonary endothelium in respiratory failure enhance lung absorption. The effects of changes in blood pH on plasma protein binding and volume of distribution are discussed, but relevant data are not available to explain the distribution changes observed in acutely ill patients. Lung diffusion of some antimicrobial agents is enhanced in patients with pulmonary infections. Decreased cardiac output and hepatic blood flow in patients under mechanical ventilation cause an increase in the plasma concentration of drugs with a high hepatic extraction ratio, such as lidocaine (lignocaine). On a theoretical basis, hypoxia should lead to decreased biotransformation of drugs with a low hepatic extraction ratio, but in vivo data with phenazone (antipyrine) or theophylline are conflicting. The effects of disease on the lung clearance of drugs are discussed but clinically relevant data are lacking. The pharmacokinetics of drugs in patients with asthma or chronic obstructive pulmonary disease are reviewed. Stable asthma and chronic obstructive pulmonary disease do not appear to affect the disposition of theophylline or beta 2-agonists such as salbutamol (albuterol) or terbutaline. Important variations in theophylline pharmacokinetics have been reported in critically ill patients, the causes of which are more likely to be linked to the poor condition of the patients than to a direct effect of hypoxia or hypercapnia. Little is known regarding the pharmacokinetics of cromoglycate, ipratropium, corticoids or antimicrobial agents in pulmonary disease. In patients under mechanical ventilation, the half-life of midazolam, a new benzodiazepine used as a sedative, has been found to be lengthened but the underlying mechanism is not well understood. Pulmonary absorption of pentamidine was found to be increased in patients under mechanical ventilation. Pharmacokinetic impairment does occur in patients with severe pulmonary disease but more work is needed to understand the exact mechanisms and to propose proper dosage regimens.     

中国患者异丙酚群体药代动力学(英文)

目的:用NONMEN程序分析中国患者群体药代动力学,并定量研究性别、年龄和体重对异丙酚药代参数的影响。方法:研究了76例择期手术的患者(男37例、女39例、年 龄19-77岁、体重39-86kg),共收集1459个血液标本。用NONMEN方法分析清除率和分布容积的个体间变异以及年龄、体重和性别的影响。结果:可用三室模型模拟异丙酚的药代动力学参数。体重可影响异丙酚的中央室、浅外周室和深外周室的清除率以及中央室的分布容积,而浅外周室和深外周室的分布容积保持不变。体重60kg的成人的上述药代参数的估计值分别为:1.56L/min、0.737L/min、0.360L/min、12.1L、43L、213L。老人随年龄的增大而清除率和中央室的分布容积减少。结论:中国人的异丙酚的药代动力学可用标准三室模型描述,年龄和体重可影响模型参数。因此根据患者的个体药代参数可改善靶控输注的精密度。     

Extended blood collection period required to define distribution and elimination kinetics of propofol.

The pharmacokinetics of propofol were investigated following bolus intravenous administration of 2-3 mg kg-1 of drug to eight surgical patients. Apparent elimination half-life, volume of distribution and systemic blood clearance of propofol correlated strongly with the sampling period, which ranged from 8 to 52 h, depending on the time taken for the propofol concentration to reach the detection limit of the assay. In the three patients in whom the sampling period exceeded 42 h, apparent elimination half-life (55.6 h) and apparent volume of distribution (1370 l) greatly exceeded previously published estimates and systemic blood clearance (1020 ml min-1) was much less than previous estimates. This suggests that previous estimates were biased by the relatively short duration of blood collection in those studies (8 to 12 h).     

厄贝沙坦、氯沙坦对兔体内环孢素A药动学的影响

目的:研究厄贝沙坦、氯沙坦对家兔体内环孢素A(CsA)药动学的影响。方法:12只家兔随机分成2组,每组6只。每组采用自身对照法,分别测定合用厄贝沙坦、氯沙坦前、后CsA的血药浓度,并对主要药动学参数进行比较。结果:与合用前比较,合用厄贝沙坦、氯沙坦后CsA的Cmax均显著升高(P<0.01),AUC0～24均显著增加(P<0.01),血浆清除率、表观分布容积均显著降低(P<0.05或P<0.01),其余药动学参数无显著性变化。结论:合用厄贝沙坦、氯沙坦后可升高CsA的血药浓度,临床上其与CsA合用需监测CsA的血药浓度,以保证治疗的安全有效。