Pharmacokinetics and pharmacodynamics of a new reformulated microemulsion and the long-chain triglyceride emulsion of propofol in beagle dogs

Background and purpose:

Microemulsion propofol was developed to eliminate lipid solvent-related adverse events of long-chain triglyceride emulsion (LCT) propofol. We compared dose proportionality, pharmacokinetic and pharmacodynamic characteristics of both formulations.

Experimental approach:

The study was a randomized, two-period and crossover design with 7-day wash-out period. Microemulsion and LCT propofol were administered by zero-order infusion (0.75, 1.00 and 1.25 mg·kg⁻¹·min⁻¹) for 20 min in 30 beagle dogs (male/female = 5/5 for each rate). Arterial samples were collected at preset intervals. The electroencephalographic approximate entropy (ApEn) was used as a measure of propofol effect. Dose proportionality, pharmacokinetic and pharmacodynamic bioequivalence were evaluated by non-compartmental analyses. Population analysis was performed using nonlinear mixed effects modelling.

Key results:

Both formulations showed dose proportionality at the applied dose range. The ratios of geometric means of AUC_last and AUC_inf between both formulations were acceptable for bioequivalence, whereas that of C_max was not. The pharmacodynamic bioequivalence was indicated by the arithmetic means of AAC (areas above the ApEn time curves) and E₀ (baseline ApEn)–E_max (maximally decreased ApEn) between both formulations. The pharmacokinetics of both formulations were best described by three compartment models. Body weight was a significant covariate for V₁ of both formulations and sex for k₂₁ of microemulsion propofol. The blood-brain equilibration rate constants (k_e0, min⁻¹) were 0.476 and 0.696 for microemulsion and LCT propofol respectively.

Conclusions and implications:

Microemulsion propofol was pharmacodynamically bioequivalent to LCT propofol although pharmacokinetic bioequivalence was incomplete, and demonstrated linear pharmacokinetics at the applied dose ranges.     

Pharmacokinetics and Pharmacodynamics of Emepronium Bromide (Cetiprin®) after Intravenous Administration in Man

Intravenous doses of 1, 5, 10 and 15 mg of emepronium bromide were given to three healthy volunteers. Emepronium serum concentration declined in a triexponential manner with half-lives between 2.2–3.0 min., 1.0–1.6 hours and 5.1–13 hours, respectively. The initial dilution space (volume of the central compartment) varied between 4.1–7.51. The area under the serum concentration time curve increased linearly with dose, indicating constancy of total serum clearance (range: 24–38 1/hr) with dose. The renal clearance of emepronium varied with serum concentration; secretion in addition to glomerular filtration was evident. Tubular secretion of emepronium was half-saturated at serum concentrations of ～ 50 nmol/l. No obvious drug-related effect on blood pressure was noted, whereas salivary secretion decreased and heart rate increased with 10–15% at emepronium serum concentrations of about 200 nmol/l. ECG recordings were without abnormalities after slow intravenous injections of emepronium bromide in doses of up to 15 mg. Since no adverse effects were noted, intravenous administration of emepronium bromide may be an alternative in situations where the drug is now used intramuscularly e.g. severe tenesmus in the urinary bladder.     

Pharmacokinetics and Pharmacodynamics of L-703,014, a Potent Fibrinogen Receptor Antagonist,After Intravenous and Oral Administration in the Dog

The pharmacokinetics and pharmacodynamics of L-703,014, a fibrinogen receptor antagonist, have been examined in the dog. An analytical method which utilizes methanol precipitation of dog plasma proteins followed by HPLC with an automated column switching technique using the chemical analogue L-704,326 as internal standard was developed for the determination of L-703,014 in dog plasma. The compound was not metabolized in the dog and was eliminated in the kidneys and into bile. Of the administered dose, 68.9 ± 1.3% (i.v.) and 80.5 ± 11.9% (p.o.) were recovered in the feces; 20.3 ± 3% (i.v.) and 2.2 ± 0.2% (p.o.) were recovered in the urine by 72 hr. L-703,014 was 23 ± 3.4% bound in dog plasma protein and the mean ratio of plasma/whole blood was 1.22 ± 0.05. The mean terminal half-life was 118 ± 36 min, the mean steady-state volume of distribution was 0.61 ± 0.22 L/kg, and the mean plasma clearance was 8 ± 2 mL/min/kg. Ex vivo platelet aggregation measurements were made by inducing platelet aggregation with 10 µg/ mL collagen in the presence of 1 µM epinephrine as an agonist. The mean C ₅₀ was 44.4 ± 6.0 ng/mL, and the mean Hill coefficient was 1.5 ± 0.3. The mean bioavailability was 4.9 ± 1.4% in dogs administered 2.0 mg/kg (p.o.).     

他汀类药物化学结构和理化性质对其药效及药动学特性的影响

他汀类药物能安全有效地降低血浆低密度脂蛋白胆固醇(LDL-C),是治疗高胆固醇血症的首选药物.已上市的他汀类药物作用机制大致相同,但化学结构有差异,导致其水溶性、亲脂亲水性不同,进而影响在人体内的吸收、分布、代谢及排泄特征.本文综述了此类药物化学结构和理化性质对其药效及药动学特性的影响.所有他汀类药物均有首过效应,因而药物可在肝脏富集.已上市药物中,瑞舒伐他汀降低LDL-C的效果较好,阿托伐他汀、辛伐他汀及普伐他汀次之.     

2%和1%丙泊酚用于腹腔镜子宫肌瘤剔除术患者的药效学比较

目的 比较2%与1%丙泊酚的实际药效关系,减少丙泊酚麻醉患者脂质输入过多引起的相关不良反应。方法 择期行腹腔镜子宫肌瘤剔除术患者82例,采用随机数字表法分为1%丙泊酚组和2%丙泊酚组,每组41例;2组丙泊酚诱导靶控血浆浓度为4 μg·mL^-1,术中靶控输注丙泊酚维持麻醉,根据脑电双频指数（bispectral index,BIS）值调整丙泊酚的靶控血浆浓度,使BIS值维持在50左右（45~55）;记录意识开始消失所需时间、意识消失时丙泊酚用量、苏醒时间和丙泊酚输注总量。结果 2%丙泊酚组意识开始消失所需时间、意识消失时丙泊酚用量和丙泊酚输注总量>1%丙泊酚组,苏醒时间<1%丙泊酚组,差异均有统计学意义（P<0.05）;2%丙泊酚组脂剂的输入量为1%丙泊酚组的59%。结论 使用2%丙泊酚靶控输注麻醉,可减少丙泊酚麻醉患者的脂质输入量,减少脂质输入过多引起的相关不良反应;2%丙泊酚的实际药效约等于1%丙泊酚的1.7倍。     

高脂食物对氨茶碱控释片药代动力学的影响

本文采用荧光偏振免疫分析法,对6名健康受试者空腹或食用高脂早餐后立即服单剂量氨茶碱控释片的血药浓度进行测定,并计算其药代动力学参数。结果表明,高脂食物显著降低氮茶碱控释片的吸收速率,T_(max)从空腹状态下的3.53±0.44h上升至6.54±2.08h(p<0.01),AUC_0→∞增加20％,但无显著差异(p>0.05)。两组的C_(max)、Ke、t_(1/2)和CL没有明显改变。提示高脂肪食物能延缓氨茶碱控释片的吸收,不影响其体内代谢过程和吸收量。由于起效时间减慢,可能会影响临床治疗效果。     

两种静脉脂肪乳剂对早产儿静脉营养相关胆汁淤积的影响

目的:研究两种静脉脂肪乳剂对早产儿静脉营养相关胆汁淤积的影响.方法:通过回顾性病例对照研究,选取某院于2018年4月～2020年2月监护室收治的早产儿140例,将所有早产儿按照随机数字表法划分为对照组(采用豆油静脉脂肪乳剂)与研究组(采用鱼油静脉脂肪乳剂)各70例,观察比较两组早产儿经静脉营养支持后胆汁淤积发生情况.结...     

高脂食物对氨茶碱控释片药代动力学的影响

目的:研究高脂食物对氨茶碱控释片药代动力学的影响。方法:采用荧光偏振免疫分析法,对6名健康受试者空腹或食用高脂早餐后立即服单剂量氨茶碱控释片的血药浓度进行测定,并计算其药代动力学参数。结果表明,高脂食物显著降低氨茶碱控释片的吸收速率,Tmax 从空腹状态下的3.53±0.44h上升至6.54±2.08h(P<0.01)。     

Pharmacokinetics and pharmacodynamics of propofol in patients undergoing abdominal aortic surgery

Available propofol pharmacokinetic protocols for target-controlled infusion (TCI) were obtained from healthy individuals. However, the disposition as well as the response to a given drug may be altered in clinical conditions. The aim of the study was to examine population pharmacokinetics (PK) and pharmacodynamics (PD) of propofol during total intravenous anesthesia (propofol/fentanyl) monitored by bispectral index (BIS) in patients scheduled for abdominal aortic surgery. Population nonlinear mixed-effect modeling was done with Nonmem. Data were obtained from ten male patients. The TCI system (Diprifusor) was used to administer propofol. The BIS index served to monitor the depth of anesthesia. The propofol dosing was adjusted to keep BIS level between 40 and 60. A two-compartment model was used to describe propofol PK. The typical values of the central and peripheral volume of distribution, and the metabolic and inter-compartmental clearance were V(C) = 24.7 l, V(T) = 112 l, Cl = 2.64 l/min and Q = 0.989 l/min. Delay of the anesthetic effect, with respect to plasma concentrations, was described by the effect compartment with the rate constant for the distribution to the effector compartment equal to 0.240 min(-1). The BIS index was linked to the effect site concentrations through a sigmoidal E(max) model with EC(50) = 2.19 mg/l. The body weight, age, blood pressure and gender were not identified as statistically significant covariates for all PK/PD parameters. The population PK/PD model was successfully developed to describe the time course and variability of propofol concentration and BIS index in patients undergoing surgery.     

异丙酚在容量控制性失血性休克猪体内的药动学研究

目的 探讨异丙酚在容量控制性失血性休克猪体内药动学的特点。方法 健康巴马小型猪12头,应用随机数字表法将其随机分为对照组和休克组。采用HPLC-荧光法测定猪静脉泵入异丙酚后不同时间点的血药浓度。根据测定的血药浓度计算异丙酚的消除半衰期(t_1/2),血浆-效应室平衡速率常数(K_e0),药时曲线面积(AUC)以及平均驻留时间(MRT)等药动学参数。结果 休克组异丙酚的血药浓度高于对照组,差异有显著性(P<0.05)。休克组最大药物浓度(C_max)高于对照组,差异有显著性(P<0.05)。休克组t_1/2较对照组延长,差异有显著性(P<0.05)。休克组MRT较对照组延长,差异有显著性(P<0.05)。休克组的K_e0、AUC较对照组增大,差异无统计学意义。结论 容量控制性失血性休克猪异丙酚的药动学特点是代谢减慢：药物的消除半衰期延长,血浆-效应室平衡速率常数增大,体内的平均驻留时间延长。     

Volterra Series in Pharmacokinetics and Pharmacodynamics

Nonparametric black-box modeling has a long successful history of applications in pharmacokinetics (PK) (notably in deconvolution), but is rarely used in pharmacodynamics (PD). The main reason is associated with the fact that PK systems are often linear in respect to drug inputs, while the reverse is true for many PK/PD systems. In the PK/PD field existing non-parametric methods can deal with linear systems, but they cannot describe non-linear systems. Our purpose is to describe a novel implementation of a general nonparametric model which can represent non-linear systems, and in particular non-linear PK/PD systems, The model is based on a Volterra series, which is an integral series expansion of the response of a system in terms of its kernels and the inputs to the system. In PK we are familiar with the first term of the Volterra series, the convolution of the first kernel of the system (the so-called PK disposition function) with drug input rates. The main advantages of higher order Volterra representations is that they are general representations and can be used to describe and predict the response of an arbitrary (PK/ PD) system without any prior knowledge on the structure of the system. The main problem of the representation is that in a non-parametric representation of the kernels the number of parameters to be estimated grows geometrically with the order of the kernel. We developed a method to estimate the kernels in a Volterra-series which overcomes this problem. The method (i) is fully non-parametric (the kernels are represented using multivariate splines), (ii) is maximum-likelihood based, (iii) is adaptive (the order of the series and the dimensionality of each kernel is selected by the method), and (iv) allows for non-equispaced observations (thus allowing a reduction of the number of parameters in the representation, and the analysis of, e.g., PK/PD observations). The method is based on an adaptation of Friedmans's Multivariate Adaptive Regression Spline method. Examples demonstrate the possible application of the approach to the analysis of different PK/PD systems.     

TC-1静脉脂肪乳剂的制备

目的 研制和生产TC-1静脉脂肪乳剂,以期为临床提供解救高血压危象的新型药物制剂。方法 处方配比为TC-1 0.5 mg·mL-1、精制蛋黄卵磷脂1.2%、甘油2.2%。注射用大豆油20%;通过初乳制备、高压匀化、灌装封口、热压灭菌等工序制得TC-1静脉脂肪乳注射液,并在（5±2）℃条件下考察制剂6个月内的稳定性。结果 3批小批量试验的检验结果,用动态光散射法测定平均粒径〈0.3 μm、粒度分布均匀、无〉1 μm粒子,稳定性均符合中国药典2010年版及日本药局方的要求。结论 确定了超高压微射流均质机-MiniDeBEE制备含药静脉脂肪乳的关键设备条件、工艺参数,解决了工程配套问题,所取得的成果有利于脂肪乳剂的生产。TC-1静脉脂肪乳注射液的成功研制,为含药静脉脂肪乳的制备及稳定性研究提供了一套切实可行的方法。     

吉西他滨的药效学与药动学及其节拍化疗研究进展

目的综述吉西他滨的药效动力学(简称药效学)与药物代谢动力学(简称药动学)及其在节拍化疗中的研究进展,为临床制定安全有效的给药方案提供借鉴。方法以"gemcitabine""pharmacodynamics""pharmacokinetics""metronomic chemotherapy"为关键词,查询PubMed及Web of Science等数据库中收录的相关文献,并从药效学作用、药动学过程、节拍化疗中的研究进展3个方面进行综述。结果与结论吉西他滨属胞嘧啶核苷类抗肿瘤药物,用于多种实体肿瘤尤其是胰腺癌与肺癌的治疗。吉西他滨是最早应用于节拍化疗的抗肿瘤药物之一,单用或与顺铂、紫杉醇等多种细胞毒类药物联用化疗效果良好,临床疗效显著。     

A Compartmental Analysis of the Pharmacokinetics of Propofol in Sheep

Conventional compartmental pharmacokinetic analysis may provide inaccurate prediction of drug concentrations after rapid iv administration. To examine this, compartment and effect compartment analysis was applied to measured arterial and brain concentrations of propofol in sheep after iv administration at a range of doses and dose rates. Although arterial and brain concentrations were reasonably well fitted to compartmental and effect compartment models for individual doses and dose rates, the structure and parameters of all models differed with changes in both dose and rate of administration. There were large discrepancies between predicted and measured arterial and brain concentrations when these models were used to predict drug concentrations across doses and dose rates. These data support the limitations of this type of modeling in the setting of rapid propofol administration.     

The Effects of Urine pH Modification on the Pharmacokinetics and Pharmacodynamics of Phenylpropanolamine

To determine whether uninary alkalinization had an effect on the plasma pharmacokinetics and pharmacodynamics of phenylpropanolamine, a double-blind crossover study was conducted in four healthy, normotensive male volunteers. The subjects received 25 mg immediate-release phenylpropanolamine and either placebo or sodium bicarbonate in a balanced randomized order. The bicarbonate treatment consisted of 6 g sodium bicarbonate 30 min prior to the phenylpropanolamine and then 3 g sodium bicarbonate every 4 hr for the next 16 hr. During the control treatment, phenylpropanolamine and a placebo for bicarbonate (lactose) were given on the same schedule. Blood and urine samples were collected over 24 hr and analyzed by HPLC. A supine blood pressure and pulse were obtained before each blood sample. The bicarbonate treatment significantly increased the urine pH throughout the study period and decreased phenylpropanolamine renal clearance by 33.5%. The apparent total-body clearance was also decreased by 31.5% and resulted in higher postabsorptive plasma phenylpropanolamine concentrations in each subject as compared to the control treatment. Both systolic and diastolic blood pressures changed significantly from baseline in both treatments. The bicarbonate treatment was accompanied by significantly higher diastolic blood pressures than in the control treatment, but there was no effect on systolic blood pressures. Generally, when the blood pressure–concentration pairs were plotted chronologically, clockwise hysteresis curves resulted. Heart rates did not change significantly from baseline values for either treatment. In this small group of normotensive healthy male volunteers, urinary alkalinization significantly depressed the renal clearance of phenylpropanolamine, producing higher postabsorptive phenylpropanolamine plasma concentrations and a small but significant increase in the diastolic blood pressure.     

Population Pharmacokinetics and Pharmacodynamics of Sotalol in Pediatric Patients with Supraventricular or Ventricular Tachyarrhythmia

Aims: To derive useful pharmacokinetic (PK) and pharmacodynamic (PD) information for guiding the clinical use of sotalol in pediatric patients with supraventricular (SVT) or ventricular tachyarrhythmia (VT).Methods: Two studies were conducted in-patients with SVT or VT in the age range between birth and 12 years old. Both studies used an extemporaneously compounded formulation prepared from sotalol HCl tablets. In the PK study, following a single dose of 30 mg/m² sotalol, extensive blood samples (n=10) were taken. The PK–PD study used a dose escalation design with doses of 10, 30, and 70 mg/m², each administered three times at 8-hr intervals without a washout. Six ECG recordings for determination of QT and RR were obtained prior to the initial dose of sotalol. Four blood samples were collected six ECG's were determined during the third interval at each dose level. Plasma concentrations of sotalol (C) were assayed by LC/MS/MS. The data analysis used NONMEM to obtain the population PK and PD parameter estimates. The individual PK and PD parameters were estimated with empirical Bayes methodology.Results: A total of 611 C from 58 patients, 477 QTc and 499 RR measurements from 23 and 22 patients, respectively, were available for analysis. The PK of sotalol was best described by a linear two-compartment model. Oral clearance (CL/F) and volume of central compartment (Vc/F) were linearly correlated with body surface area (BSA), body weight or age. CL/F was also linearly correlated with creatinine clearance. The best predictor for both CL/F and Vc/F was BSA. The remaining intersubject coefficients of variation (CV's) in CL/F, and Vc/F were 21.6% and 20.3%, respectively. The relationship of QTc to C was adequately described by a linear model. The intersubject CV's in slope (SL) and intercept (E0) were 56.2 and 4.7%, respectively. The relationship of RR to C was also adequately described by a linear model in which the baseline RR and SL were related to age or BSA. The intersubject CV's for SL and E₀ were 86.7 and 14.4%, respectively.Conclusions: BSA is the best predictor for the PK of sotalol. Both QTc and RR effects are linearly related to C. No covariates are found for the QTc–C relation, while the RR–C relation shows age or BSA dependency.     

新型麻醉药异丙酚静注乳剂的制备及其物理性质的测定

用国产原料制备了异丙酚静注乳剂，并对其一些物理性质进行了测定．结果表明该制剂的粒度分布、ｐＨ值、渗透压等项均符合静脉注射制剂的要求     

毛兰素注射液在大鼠体内药动学研究

目的阐明毛兰素注射液在SD大鼠体内药动学规律。方法 SD大鼠分别单次和隔天、每隔一个半衰期一次多剂量静脉注射毛兰素注射液。采用高效液相色谱-质谱联用（HPLC-MS）测定大鼠静脉注射后不同时间大鼠血浆中毛兰素的血药浓度。结果大鼠单次静脉注射25,50,100mg·kg-1毛兰素注射液的主要药动学参数为：T1/2β分别为3.66,3.75,3.89h;AUC0-12分别为1453.0,3041.6,6731.6ng·mL-1·h;AUC0-∞分别为1462.0,3077.3,6788.7ng·mL-1·h;Vd分别为11.67,10.37,3.38L·kg-1;CL分别为0.049,0.089,0.024L·kg-1·h-1;MRT分别为0.18,0.28,0.21h;50mg·kg-1剂量的毛兰素注射液隔日给药5次其药动学参数与单次给药相近;而50mg·kg-1剂量的毛兰素注射液每隔一个半衰期一次给药5次的T1/2β为5.43h,AUC（S0）（0-t）为9800.8ng·mL-1·h。结论毛兰素注射液在大鼠体内的动力学过程与剂量相关,毛兰素注射液单剂量给药的体内药动学符合开放型二房室模型,T1/2β与给药剂量与关,表明毛兰素在大鼠体内的消除过程符合一级动力学规律。隔日多剂量给药的消除过程亦符合一级动力学规律;而每隔一个半衰期一次多剂量给予50mg·kg-1剂量的毛兰素其在大鼠体内则呈非线性消除。     

复方丹参滴丸对华法林在人体内药动学和药效学的影响

目的研究复方丹参滴丸对华法林在人体内药动学和药效学的影响,以及单独服用复方丹参滴丸4周后对凝血酶原时间(PT)和活化部分凝血活酶时间(APTT)的影响。方法采用随机、单盲、双周期交叉、安慰剂对照试验设计。12名男性健康志愿者随机分为2组(6人/组),连续5周每日分别服用复方丹参滴丸(10片,每天3次)或安慰剂(10片,每天3次);d29口服单剂量华法林5 m g;第2周期2组交叉服用安慰剂或复方丹参滴丸,其余给药方案不变。按要求收集志愿者血样,分别以高效液相色谱法(H PLC)测定华法林的血药浓度以及半自动血凝仪测定常见凝血指标。结果合用复方丹参滴丸后,华法林的药动学参数cmax、AUC0~144、AUC0~∞、t1/2显著增加(P<0.05),CL/F显著减小(P<0.05),tmax和V/F没有显著变化;华法林的药效学参数发生显著变化。单独服用复方丹参滴丸4周后,PT和APTT均发生显著变化。结论复方丹参滴丸可影响华法林的药动学和药效学;单独服用复方丹参滴丸4周对凝血功能有显著影响。     

Facilitation of Pulmonary Insulin Absorption by H-MAP: Pharmacokinetics and Pharmacodynamics in Rats

Purpose. Several low molecular weight amino acids have previously been reported to enable the oral delivery of proteins. In the present studies, the effect of H-MAP (hydroxy methyl amino propionic acid) on the pharmacokinetics (PK) and pharmacodynamics (PD) of porcine insulin delivered to the lungs of rats by spray-instillation (SI) has been determined. Methods. Aliquots (100 l) of increasing doses of porcine insulin alone (0.26, 1.3, 2.6, 13, and 26 U/kg) or combined with increasing doses of H-MAP (5, 10, 16, and 25 mg/kg), at pH 7.2-7.6 were administered intratracheally to fasted anesthetized rats using a micro spray-instillator. Blood samples were collected from the jugular vein at specified intervals and the plasma concentrations of insulin and glucose were determined. The PK and PD of porcine insulin alone following subcutaneous (SC) administration of increasing doses were also determined. Results. The PK of insulin administered either by SI to the lungs or SC injection were absorption rate dependent, resulting in post-peak half-lives 10 to 25-fold greater than the reported intravenous elimination half-life (3 min). The relative bioavailability (F') of insulin administered alone by SI varied from 23.8 to 80% for the lowest and highest insulin dose, respectively. Co-administration of H-MAP and insulin to the lungs significantly changed the PK and PD of insulin in a dose dependent fashion. Maximum PK and PD responses were obtained at an H-MAP dose of 16 mg/kg and an insulin dose of 1.3 U/kg. At this combination, the relative bioavailability of insulin was increased more than 2.5 fold, maximum concentration (C_max) increased 2-fold and the minimum plasma glucose concentration (%MPGC) was reduced more than 2-fold with respect to same dose of insulin alone. A greater total reduction in plasma glucose (%TRPG_0t) was achieved for H-MAP/insulin combination (66 ± 5 %) compared to insulin alone (47 ± 10 %). Conclusion. H-MAP has potential for increasing the pulmonary bioavailability of insulin administered through the lungs.