头孢硫脒与头孢硫脒盐药动学及相对生物利用度研究

目的研究家兔肌注头孢硫脒和头孢硫脒盐的药动学及相对生物利用度。方法健康家兔12只,随机分为2组,分别肌肉注射等摩尔药物,以高效液相色谱法测定血药浓度,以Matlab程序分析计算药动学参数及相对生物利用度,判断两种制剂的生物等效性。结果头孢硫脒和头孢硫脒盐的平均血药峰浓度(cmax)分别为(0.106±0.034)和(0.075±0.019)mmol/L,曲线下面积(AUC)分别为(6.887±1.660)和(6.293±0.707)mmol.min/L,达峰时间(Tmax)分别为(9.697±1.753)和(10.758±3.196)min,血浆清除半衰期(T1/2)分别为(39.908±10.532)和(51.547±9.383)min。两种制剂的药-时曲线吻合良好,所得主要药动学参数经统计学处理,P值均>0.05,无显著性差异,头孢硫脒与头孢硫脒盐比较的相对生物利用度为109.4%。结论头孢硫脒与头孢硫脒盐为生物等效制剂。     

HPLC法测定头孢硫脒大鼠体内分布浓度及其药动学研究

目的建立大鼠体内头孢硫脒血药浓度和分布浓度的测定方法及进行药动学研究。方法采用高效液相色谱技术测定不同剂量(200.92m g/kg,100.46m g/kg)头孢硫脒大鼠体内不同时间的血药浓度和药物分布浓度。C18反相色谱柱(Hypersil,250nm×4.0nm,5μm),流动相为乙腈∶磷酸盐缓冲液(20∶80)。结果在0.20~50μg/m l范围内呈良好线性关系,r>0.997,定量限为0.20μg/m l,回收率在95.91%~103.1%。大鼠静注头孢硫脒后,体内分布以膀胱、甲状腺、关节腔、皮肤、前列腺、肾上腺、胃、十二指肠、肾、子宫、淋巴结、眼球、卵巢、肺等脏器的浓度较高,脑、睾丸、脂肪、脾等脏器的浓度较低,主要经尿排泄,约占给药量的95%;体内药动学呈开放二室模型,主要药动学参数如下:t1/2α0.2950,0.2711h;t1/2β1.345,1.327h;CL 4.284、4.254L/h;V c0.5540、0.4901L/kg;V 2.077、2.035L/kg;AUC 23.62和46.92(m g.h)/L。头孢硫脒高、低剂量药动学参数值非常相近,表明在高、低剂量范围内药物呈线性动力学特征。结论本方法适用于药动学研究,测定结果为临床合理用药提供了依据。     

注射用头孢硫脒的稳定性研究

目的考察注射用头孢硫脒的稳定性。方法按药典规定的方法进行考察。结果在不同条件下注射用头孢硫脒的性状、含量、酸度、有关物质、澄清度与颜色、水分、不溶性微粒等均符合规定。结论注射用头孢硫脒具有良好的稳定性。     

头孢硫脒所致不良反应文献概述

头孢硫脒为第一代头孢菌素,对金黄色葡萄球菌、草绿色链球菌、肺炎球菌的作用较强。近年来国内有文献报道其不良反应,现概述如下:1过敏反应黄静等报道,患男,46岁,因急性支气管炎给予头孢硫脒2g+0.9%NS100ml静滴,约10分钟后患者颜面及颈部出现直径约0.5cm白色突出皮肤,周围散在红疹的小突起,伴轻度瘙痒感,即停药,予抗过敏对症治疗,30分钟后皮疹逐渐消退[1]。     

注射用头孢硫脒的稳定性研究

目的考察注射用头孢硫脒的稳定性。方法建立注射用头孢硫脒的含量测定方法,并进行加速试验及室温留样试验,考察其外观、含量、pH值等变化。结果加速试验及室温留样试验中其样品各项指标与0d相比无明显变化。结论注射用头孢硫脒具有良好的稳定性。     

头孢硫脒的合成方法改进

1,3－二异丙基脒基2－硫代－乙酸盐酸盐经Vilsmeier试剂活化后,与带有保护基的7－ACA缩合得到头孢硫脒,收率由45％提高到56％,本方法操作简便,适宜于规模生产。     

头孢硫脒纯化新方法

将头孢硫脒粗品和二环己胺反应得头孢硫脒二环己胺盐,所得胺盐用水和四氢呋喃(THF)作溶剂,用盐酸调节溶液pH至4.5,滴加THF,头孢硫脒结晶析出。所得的头孢硫脒纯度高、稳定性好。该方法可用于纯化头孢硫脒及对照品的制备。     

头孢硫脒合成工艺改进

目的 研究头孢硫脒的合成工艺,使之适合工业化生产,并提高收率。方法 以7-ACA为原料,与溴乙酰溴在低温、碱性条件下经C-7位上的氨基酰化,再同侧链二异丙基硫脲缩合制得头孢硫脒。结果 总收率由45%提高到62%,产物经IR,MS,1H-NMR确证结构。结论 改进后的工艺过程大为简化,总收率得到了提高,适合于工业化生产。     

头孢硫脒合成工艺改进

目的研究头孢硫脒的合成工艺,使之适合工业化生产,并提高收率。方法以7-ACA为原料,与溴乙酰溴在低温、碱性条件下经C-7位上的氨基酰化,再同侧链二异丙基硫脲缩合制得头孢硫脒。结果总收率由45%提高到62%,产物经IR,MS,1H-NMR确证结构。结论改进后的工艺过程大为简化,总收率得到了提高,适合于工业化生产。     

头孢硫脒在门诊儿科应用

目的了解本院儿科门诊头孢硫脒使用情况,为合理使用头孢硫脒提供参考。方法抽查本院2010年10月至2010年4月我院儿科诊治患者225例,其中上呼吸道感染患者93例,支气管炎患者78例,肺炎患者54例。根据感染程度给予头孢硫脒静脉滴注相应疗程。结果头孢硫脒在治疗儿童上呼吸道感染有效率100％,儿童支气管炎有效率93．58％治疗有效率94．44％,不良反应少。结论头孢硫脒治疗儿童上呼吸道感染,儿童支气管炎,儿童肺炎,疗效显著,建议儿童使用前先做皮试,促进抗菌药物的合理应用。     

Physiologically based pharmacokinetic modeling of cyclotrimethylenetrinitramine in male rats

A physiologically based pharmacokinetic (PBPK) model for simulating the kinetics of cyclotrimethylene trinitramine (RDX) in male rats was developed. The model consisted of five compartments interconnected by systemic circulation. The tissue uptake of RDX was described as a perfusion‐limited process whereas hepatic clearance and gastrointestinal absorption were described as first‐order processes. The physiological parameters for the rat were obtained from the literature whereas the tissue : blood partition coefficients were estimated on the basis of the tissue and blood composition as well as the lipophilicity characteristics of RDX (logP = 0.87). The tissue : blood partition coefficients (brain, 1.4; muscle, 1; fat, 7.55; liver, 1.2) obtained with this algorithmic approach were used without any adjustment, since a focused in vitro study indicated that the relative concentration of RDX in whole blood and plasma is about 1 : 1. An initial estimate of metabolic clearance of RDX (2.2 h^?1 kg^?1) was obtained by fitting PBPK model simulations to the data on plasma kinetics in rats administered 5.5 mg kg^?1 i.v. The rat PBPK model without any further change in parameter values adequately simulated the blood kinetic data for RDX at much lower doses (0.77 and 1.04 mg ^?1 i.v.), collected in this study. The same model, with the incorporation of a first order oral absorption rate constant (K_a 0.75 h^?1), reproduced the blood kinetics of RDX in rats receiving a single gavage dose of 1.53 or 2.02 mg kg^?1. Additionally, the model simulated the plasma and blood kinetics of orally administered RDX at a higher dose (100 mg kg^?1) or lower doses (0.2 or 1.24 mg kg^?1) in male rats. Overall, the rat PBPK model for RDX with its parameters adequately simulates the blood and plasma kinetic data, obtained following i.v. doses ranging from 0.77 to 5.5 mg kg^?1 as well as oral doses ranging from 0.2 to 100 mg kg^?1. Published in 2009 by John Wiley & Sons, Ltd.     

Physiologically based pharmacokinetic model for pralmorelin hydrochloride in rats.

Pralmorelin hydrochloride (pralmorelin), consisting of six amino acid residues, is a growth hormone-releasing peptide. The aim of this study is to analyze the pharmacokinetics of pralmorelin after intravenous bolus administration to rats, and to develop a physiologically based pharmacokinetic (PB-PK) model to describe and predict the concentrations of pralmorelin in blood and tissues. Pralmorelin (3 mg/kg) was administered intravenously to 24 Sprague-Dawley rats. Groups of three rats were sacrificed by decapitation at each designated time point (up to 4 h), and plasma and tissues (brain, lung, heart, liver, kidney, small intestine, muscle, adipose, and skin) were collected. Bile was also pooled until decapitation. The concentration of pralmorelin in samples was determined by liquid chromatography-tandem mass spectrometry. Plasma concentrations of pralmorelin declined rapidly in a biexponential manner. Biliary excretion of pralmorelin was so rapid that 80% of the dose was recovered unchanged in the bile within 1 h after administration. The distribution parameters in each tissue were obtained by using a hybrid model and an integration plot. They revealed that the distribution of pralmorelin into liver was blood flow-limited, and its distribution was permeability-limited in all other tissues. The PB-PK model developed in this study well described the time courses of pralmorelin concentration in the blood and tissues of rats.     

Physiologically based pharmacokinetic modeling of dibromoacetic acid in F344 rats

A novel physiologically based pharmacokinetic (PBPK) model structure, which includes submodels for the common metabolites (glyoxylate (GXA) and oxalate (OXA)) that may be involved in the toxicity or carcinogenicity of dibromoacetic acid (DBA), has been developed. Particular attention is paid to the representation of hepatic metabolism, which is the primary elimination mechanism. DBA-induced suicide inhibition is modeled by irreversible covalent binding of the intermediate metabolite α-halocarboxymethylglutathione (αH1) to the glutathione-S-transferase zeta (GSTzeta) enzyme. We also present data illustrating the presence of a secondary non-GSTzeta metabolic pathway for DBA, but not dichloroacetic acid (DCA), that produces GXA. The model is calibrated with plasma and urine concentration data from DBA exposures in female F344 rats through intravenous (IV), oral gavage, and drinking water routes. Sensitivity analysis is performed to confirm identifiability of estimated parameters. Finally, model validation is performed with data sets not used during calibration. Given the structural similarity of dihaloacetates (DHAs), we hypothesize that the PBPK model presented here has the capacity to describe the kinetics of any member or mixture of members of this class in any species with the alteration of chemical-and species-specific parameters.     

Physiologically relevant two-compartment pharmacokinetic models for skin

Pharmacokinetic (compartment) models for skin have been used to predict or analyze absorption of chemical into and through skin. For highly lipophilic chemicals, the stratum corneum (sc) and the viable epidermis (v.e.) both contribute a significant resistance to chemical penetration and thus, both should be included in the model. This paper describes two-compartment models that represent the sc and the ve separately by extending the procedures previously developed for one-compartment models. The two-compartment models described here were developed by matching characteristics of a two-membrane model of skin. These compartment models were compared with membrane representations of the s.c. and v.e. for several different dermal exposure scenarios. When valid, which it is for many chemical exposure scenarios, the two-compartment model developed using characteristic times of the membrane model (model B2) more closely represents the two-membrane model than the model developed with equilibrium conditions of the membrane model (model B1). When model B2 is invalid, then model B1 is recommended. Criteria are provided for choosing from the various one- or two-compartment model options.     

Physiologically based pharmacokinetic model for topotecan in mice

Topotecan is a chemotherapeutic agent of choice for the second-line treatment of recurrent ovarian cancer. In this article, we have developed a physiologically based pharmacokinetic model to characterize and predict topotecan concentrations in mouse plasma and tissues. Single intravenous (IV) doses (5, 10 and 30 mg/kg) of topotecan were administered to male Swiss Webster mice, with plasma and tissue samples collected over 24 h, and with sample analysis by high performance liquid chromatography. Topotecan disposition in the lungs, heart, muscle, skin, spleen, gut, liver, brain and adipose was described by perfusion rate-limited compartments, whereas the testes and intraperitoneal (IP) fluid were described with permeability rate-limited compartments. The kidneys were modeled as a permeability rate-limited compartment with nonlinear efflux. The model included enterohepatic recycling of topotecan, with re-absorption of drug secreted in the bile and nonlinear bioavailability. Topotecan demonstrated dose-dependent, nonlinear pharmacokinetics and its elimination was described by nonlinear clearance from the liver and a parallel nonlinear and linear clearance from the kidneys. Mean tissue-to-plasma partition coefficients ranged from 0.123 (brain) to 55.3 (kidney). The model adequately characterized topotecan pharmacokinetics in plasma and tissue for all three doses. Additionally, the model provided good prediction of topotecan pharmacokinetics from several external data sets, including prediction of topotecan tissue pharmacokinetics following administration of 1 or 20 mg/kg IV, and prediction of plasma pharmacokinetics following doses of 1, 1.25, 15, 20 and 80 mg/kg IV and 20 mg/kg IP.     

Physiologically based pharmacokinetic model for vinylidene chloride

Vinylidene chloride (VDC), a potent hepatotoxin and suspected carcinogen, is metabolized by mixed-function oxidases into a reactive metabolite(s) which is responsible for its toxicity. The metabolite is detoxified by glutathione (GSH), and liver GSH status is an important factor in the expression of VDC toxicity. A physiologically based pharmacokinetic (PB-PK) model has been developed for VDC in the rat based on oxidative metabolism of VDC and subsequent GSH detoxification of metabolite. The model offers insight into the complex interrelationship between the processes of absorption, metabolism, and GSH conjugation, and simulates the manner in which these factors operate in regulating VDC toxicity. The PB-PK model successfully predicts blood, tissue, and exhaled air concentrations of VDC, and liver GSH levels as a function of dose and route of administration. The model also explains the complex dose-response mortality curves seen with VDC. Because of the low blood:air partition coefficient of VDC and its saturable metabolism, the amount of VDC dose that is metabolized is sensitive to the rate of absorption. After an intravenous bolus dose, most of the administered VDC is exhaled unchanged within a few minutes. Blood VDC half-life is not representative of metabolism rates but to reequilibration of VDC from fat. Rats with greater fat content, therefore, display longer VDC blood half-lives. Simulations are shown to demonstrate the strength of PB-PK modeling techniques in understanding the kinetic behavior of VDC in the rat under a variety of experimental conditions.     

Physiologically based pharmacokinetic models: integration of in silico approaches with micro cell culture analogues

There is a large emphasis within the pharmaceutical industry to provide tools that will allow early research and development groups to better predict dose ranges for and metabolic responses of candidate molecules in a high throughput manner, prior to entering clinical trials. These tools incorporate approaches ranging from PBPK, QSAR, and molecular dynamics simulations in the in silico realm, to micro cell culture analogue (CCAs)s in the in vitro realm. This paper will serve to review these areas of high throughput predictive research, and highlight hurdles and potential solutions. In particular we will focus on CCAs, as their incorporation with PBPK modeling has the potential to replace animal testing, with a more predictive assay that can combine multiple organ analogs on one microfluidic platform in physiologically correct volume ratios. While several advantages arise from the current embodiments of CCAS in a microfluidic format that can be exploited for realistic simulations of drug absorption, metabolism and action, we explore some of the concerns with these systems, and provide a potential path forward to realizing animal-free solutions. Furthermore we envision that, together with theoretical modeling, CCAs may produce reliable predictions of the efficacy of newly developed drugs.     

Physiologically based pharmacokinetic model for methanol in rats, monkeys, and humans.

The pharmacokinetics of methanol and formate were characterized in male Fischer-344 rats and rhesus monkeys exposed to methanol vapor concentrations between 50 and 2000 ppm for 6 hr. End-of-exposure blood methanol concentrations were not directly proportional to the atmospheric concentration. The methanol exposures did not cause an elevation in blood formate concentrations. After an intravenous dose of [14C]methanol in rats, metabolism, exhalation, and renal excretion contributed 96.6, 2.6, and 0.8%, respectively, to the elimination of blood methanol concentrations. These values and the calculated renal methanol extraction efficiency (0.007) are nearly identical to those for humans after low doses of methanol. A physiologically based pharmacokinetic model was developed to simulate the in vivo data. In order to simulate the observed blood methanol concentrations in the inhalation studies in rats, a double pathway for methanol metabolism to formaldehyde was used. One path used rodent catalase Km and Vmax values and the other used a smaller Km and Vmax to simulate an enzyme with a higher affinity and lower capacity. The lack of proportionality observed in end-of-exposure blood methanol concentrations may be due to saturation of an enzyme with higher affinity and lower capacity than catalase. The physiologically based pharmacokinetic model was modified to simulate the monkey data and was scaled-up for humans. In order to simulate the monkey blood methanol concentrations, the use of rodent catalase parameters for methanol metabolism was required. This finding suggests that primates and rodents may be similar in the initial step of methanol metabolism after low methanol doses. Previously published human urinary methanol excretion data was successfully simulated by the model. The models were used to predict the atmospheric methanol concentration range over which the laboratory species exhibit quantitative similarities with humans. Below 1200 ppm, all three species exhibit similar end-of-exposure blood methanol concentrations and a linear relationship between atmospheric and blood methanol concentrations. At higher atmospheric concentrations, external and internal methanol concentrations increase desparately, suggesting that delivered dose rather than exposure concentration should be used in interpreting data from high-dose studies.     

Physiologically based pharmacokinetic modeling of arsenic in the mouse

A remarkable feature of the carcinogenicity of inorganic arsenic is that while human exposures to high concentrations of inorganic arsenic in drinking water are associated with increases in skin, lung, and bladder cancer, inorganic arsenic has not typically caused tumors in standard laboratory animal test protocols. Inorganic arsenic administered for periods of up to 2 yr to various strains of laboratory mice, including the Swiss CD-1, Swiss CR:NIH(S), C57Bl/6p53(+/-), and C57Bl/6p53(+/+), has not resulted in significant increases in tumor incidence. However, Ng et al. (1999) have reported a 40% tumor incidence in C57Bl/6J mice exposed to arsenic in their drinking water throughout their lifetime, with no tumors reported in controls. In order to investigate the potential role of tissue dosimetry in differential susceptibility to arsenic carcinogenicity, a physiologically based pharmacokinetic (PBPK) model for inorganic arsenic in the rat, hamster, monkey, and human (Mann et al., 1996a, 1996b) was extended to describe the kinetics in the mouse. The PBPK model was parameterized in the mouse using published data from acute exposures of B6C3F1 mice to arsenate, arsenite, monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) and validated using data from acute exposures of C57Black mice. Predictions of the acute model were then compared with data from chronic exposures. There was no evidence of changes in the apparent volume of distribution or in the tissue-plasma concentration ratios between acute and chronic exposure that might support the possibility of inducible arsenite efflux. The PBPK model was also used to project tissue dosimetry in the C57Bl/6J study, in comparison with tissue levels in studies having shorter duration but higher arsenic treatment concentrations. The model evaluation indicates that pharmacokinetic factors do not provide an explanation for the difference in outcomes across the various mouse bioassays. Other possible explanations may relate to strain-specific differences, or to the different durations of dosing in each of the mouse studies, given the evidence that inorganic arsenic is likely to be active in the later stages of the carcinogenic process.     

Physiologically based pharmacokinetic modeling of 1,4-Dioxane in rats, mice, and humans.

1,4-Dioxane (CAS No. 123-91-1) is used primarily as a solvent or as a solvent stabilizer. It can cause lung, liver, and kidney damage at sufficiently high exposure levels. Two physiologically based pharmacokinetic (PBPK) models of 1,4-dioxane and its major metabolite, hydroxyethoxyacetic acid (HEAA), were published in 1990. These models have uncertainties and deficiencies that could be addressed and the model strengthened for use in a contemporary cancer risk assessment for 1,4-dioxane. Studies were performed to fill data gaps and reduce uncertainties pertaining to the pharmacokinetics of 1,4-dioxane and HEAA in rats, mice, and humans. Three types of studies were performed: partition coefficient measurements, blood time course in mice, and in vitro pharmacokinetics using rat, mouse, and human hepatocytes. Updated PBPK models were developed based on these new data and previously available data. The optimized rate of metabolism for the mouse was significantly higher than the value previously estimated. The optimized rat kinetic parameters were similar to those in the 1990 models. Only two human studies were identified. Model predictions were consistent with one study, but did not fit the second as well. In addition, a rat nasal exposure was completed. The results confirmed water directly contacts rat nasal tissues during drinking water under bioassay conditions. Consistent with previous PBPK models, nasal tissues were not specifically included in the model. Use of these models will reduce the uncertainty in future 1,4-dioxane risk assessments.