Pharmacokinetics of methyl parathion: a comparison following single intravenous,oral or dermal administration

Assessment of the risks posed by the residential use of methyl parathion requires an understanding of its pharmacokinetics after different routes of exposure. Thus, studies were performed using adult female rats to define the pharmacokinetic parameters for methyl parathion after intravenous injection and to apply the described model to an examination of its pharmacokinetics after single oral or dermal exposure. The pharmacokinetics of methyl parathion after intravenous administration (1.5 mg/kg) were best described by a three-compartment model; the apparent volume of the central compartment was 1.45 liters/kg, clearance was 1.85 liters/h/kg and the terminal half-life was 6.6 h with an elimination constant of 0.50 h(-1). The apparent oral absorption coefficient for methyl parathion (1.5 mg/kg) was 1.24 h(-1), and its oral bioavailability was approximately 20%. The latter likely includes a significant first pass effect. Concentrations of methyl parathion increased during the initial 10-60 min and then declined during the next 15-36 h. After dermal administration (6.25-25 mg/kg), methyl parathion concentrations peaked within 12-26 h and then declined dose dependently. The apparent dermal absorption coefficient was approximately 0.41 h(-1), and only two pharmacokinetic compartments could be distinguished. In conclusion, the pharmacokinetics of methyl parathion are complex and route dependent. Also, dermal exposure, because of sustained methyl parathion concentrations, may pose the greatest risk.     

A HPLC-UV method for the determination of puerarin in rat plasma after intravenous administration of PEGylated puerarin conjugate

A sensitive and reproducible HPLC method for quantitative determination of puerarin (PUE) in rat plasma was developed and validated using 4-hydroxybenzaldehyde as an internal standard. The separation of PUE was performed on a CAPCELL PAK C18 column by gradient elution with 0.2% aqueous phosphoric acid and acetonitrile as the mobile phase. The method was validated and found to be linear in the range of 80-12,000ng/mL. The limit of quantification was 80ng/mL based on 100μL of plasma. The variations for intra- and inter-day precision were less than 8.3%, and the accuracy values were between 98% and 105.2%. The extraction recoveries were more than 85%. The method was successfully applied in the comparative study of pharmacokinetics of PEGylated puerarin (PEG-PUE) versus PUE in rats. Compared with PUE, PEG-PUE showed a 5.2-fold increase in half-life of PUE and a 4.7-fold increase in mean residence time. In addition, this method was also successfully applied to determine the low plasma concentration of PUE regenerated from PEG-PUE in vitro.     

Identification of a biomarker for propetamphos and development of a biological monitoring assay

This paper describes the identification of a human metabolite of propetamphos ((E-O-2-isopropylcarbonyl-1-methylvinyl-O-methylethylphosphoramidothioate), formed by the hydrolytic cleavage of the enol-vinyl-phosphate bond, and the development of an analytical method suitable for biological monitoring of propetamphos exposure. The metabolite has been detected in the urine of exposed workers but not in that of control subjects. The analytical method involves azeotropic distillation of the urine with acetonitrile, followed by derivatization with pentafluorobenzyl bromide and analysis using gas chromatography with flame photometric detection.     

Pharmacokinetics of ciprofloxacin in sheep following intravenous and subcutaneous administration

Pharmacokinetics of ciprofloxacin was studied in sheep after intravenous and subcutaneous administration at a dose of 10 mg kg⁻¹. Blood was collected using indwelling jugular catheter at predetermined time intervals. Plasma was extracted and analyzed for ciprofloxacin by reverse phase high performance liquid chromatography. Following i.v. and s.c. administration, ciprofloxacin followed two-compartment and one-compartment open model, respectively. Subcutaneous route was found to possess a very low bioavailability of 40%. Ciprofloxacin was found to exert its pharmacological effect for more than 28 and 14 h after i.v. and s.c. administration, respectively.     

The formation of heart DNA adducts in F344 rat following dietary administration of heterocyclic amines

Most heterocyclic amines formed during the cooking of meat and fish have been shown to form adducts in the livers of rats. Recently, however, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), administered in the diet to Fischer 344 (F344) rats for 4 weeks, was shown to produce the highest levels of adducts in the heart. In the present study 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo [4,5-f]quinoxaline (MeIQx), 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 2-amino-6-methyldipyrido[1,2-a:1',2'-d]imidazole (Glu-P-1) were given to F344 rats at carcinogenic dose levels (IQ 0.03%, MeIQx 0.04%, Trp-P-1 0.015%, Glu-P-1 0.05%) in the diet for 4 weeks. DNA adducts in the liver and heart were analyzed by 32P-postlabeling. DNA adducts were demonstrated to appear in the hearts of all animals exposed to heterocyclic amines at the following levels: IQ, 1.8 adducts/10(7) nucleotides, MeIQx, 3.8/10(7) ntd, Trp-P-1, 20/10(7) ntd and Glu-P-1, 7.2/10(7) ntd. Values for the heart were 10-20% of the respective liver adduct levels. Heart adducts increased linearly throughout the observed period when MeIQx was administered for up to 40 weeks. When MeIQx feeding was discontinued after 20 weeks and the animals subsequently given the basal diet, the adduct level at 20 weeks did not change during the following 20 weeks. A possible role for heart DNA alterations caused by food-borne heterocyclic amines in the development of age-related myopathies and cardiovascular disease is not inconceivable.     

Kinetics of amiloride in rat following oral and intravenous administration

The disposition profile of amiloride, a potassium sparing agent, was studied in rats by using an HPLC method coupled to spectrofluorometric detection. Amiloride was administered orally and intravenously at the dose of 10 mg/Kg. The most relevant pharmacokinetic parameters are described for both administration routes.     

Morphometrical and intracellular changes in rat ovaries following chronic administration of ghrelin

The aim of our investigation was to examine the influence of chronic administration of ghrelin on the rat ovarian state. Morphometrical and intracellular changes in the ovary of 35-d female Wistar rats after sc injection of 1 nmol of ghrelin for 10 consecutive days were studied. Control animals (n = 10) were injected with normal saline using similar method. The ovaries were collected on days 1 and 6 after last injection from each group and subjected to light microscopic morphometric and electron microscopic analysis. It was demonstrated that the number of corpora lutea was significantly lower and the number of ovarian follicles was higher in the treated group on days 1 and 6, than in control (P < 0.01). Moreover, the mean diameter of each follicle, corpora lutea, luteal cell, theca layer, oocyte and zona plucida, but not of granulosa layer, as well as the whole ovarian volume were significantly lower in the treated animals at days 1 and 6 (P < 0.05). Electron microscopic analysis also indicated some intracellular changes associated with apoptosis and cell death such as presence of secondary lysosome, apoptotic bodies, nuclear chromatin condensation as well as margination, nuclear segmentation and vacuolization of cytoplasm of granulosa and theca cells. Our observations provides novel evidences for inhibitory influence of ghrelin on rat ovarian structures and, therefore, for the role of ghrelin as suppressor of female reproductive system.     

A comparison of cholinesterase activity after intravenous, oral or dermal administration of methyl parathion

Time-dependent changes in blood cholinesterase activity caused by single intravenous, oral or dermal administration of methyl parathion to adult female rats were defined. Intravenous and oral administration of 2.5 mg/kg methyl parathion resulted in rapid (<60 min) decreases in cholinesterase activity which recovered fully in vivo within 30-48 h. In contrast, spontaneous reactivation of cholinesterase in vitro was complete within 6 h at 37 degrees C. Dermal administration of methyl parathion caused dose-dependent inhibition of cholinesterase activity which developed slowly (> or =6 h) and was prolonged (> or =48 h). Time- and route-dependent effects of methyl parathion on cholinesterase activity in brain and other tissues generally paralleled its effects on activity in blood. In conclusion, pharmacodynamics of methyl parathion differ substantially with route of exposure. Recovery of cholinesterase in vivo after intravenous or oral exposure may partially reflect spontaneous reactivation and suggests a rapid clearance of methyl parathion or its active metabolite methyl paraoxon. The more gradual and prolonged inhibition of cholinesterase caused by dermal administration is consistent with disposition of methyl parathion at a site from which it or methyl paraoxon is only slowly distributed. Thus, dermal exposure to methyl parathion may pose the greatest risk for long-term adverse effects.     

F344大鼠常见非增殖性病变病理学观察

目的建立F344大鼠自发性非增殖性病变背景数据,为药物安全性评价提供基础。方法 SPF级F344大鼠336只,雌雄各半,8周龄,本中心屏障环境下饲养,随机分为4个组,分别于6、12、18和24个月4个时间点处死动物32、64、64、176只,常规病理学取材制片后显微镜检查,观察统计四个时间点动物自发性病变的病变类型和发病率。结果主要的非增殖性病变包括乳头肌纤维化、肺细支气管旁慢性炎症、肾脏病变包括肾小管扩张、蛋白管型、肾小管萎缩和钙沉积等,睾丸精子生成障碍、卵巢生长卵泡数量减少等生殖器官组织的退行性改变等。结论在本中心现有条件下,随动物生存期的延长,F344大鼠自发性非增殖性疾病病变程度和发病率均有所增加。本实验丰富了F344大鼠自发性病变的背景资料,为药物安全性评价提供基础。     

F344／N－Smu－D大鼠生长发育若干生物学特性的检测

Ｆｉｓｃｈｅｒ３４４大鼠在国外广泛应用于肿瘤研究与慢性毒性试验,八十年代中期引入我国。我们对Ｆ３４４／Ｎ－Ｓｍｕ－Ｄ大鼠的生长发育的若干生物学特性进行了检测。结果表明,该品系大鼠体型较ＳＤ大鼠与Ｗｉｓｔａｒ大鼠小,除睾丸、垂体、肾上腺、乳腺外的大部分器官与组织的自发性肿瘤的发生率相对较低,将Ｆ３４４／Ｎ－Ｓｍｕ－Ｄ大鼠种群与Ｆ３４４／ＤｕＣｒｊ种群比较,在体重、耗食量,血液学与生化学等方面的若干特性差异较大,肿瘤发生率与死亡差别不大。     

Efficient collection and cryopreservation of embryos in F344 strain inbred rats

In rats, it is now possible to produce genetically engineered strains, not only as transgenic animals but also using gene knockout techniques. Reproductive technologies have been used as indispensable tools to produce and maintain these novel valuable strains. Although studies for collecting and cryopreserving embryos have been reported using outbred rats, efficient methods have not been established in inbred strains. The F344 inbred strain is important in rat breeding and has been used for the production of transgenic/knockout strains and for genome sequencing. Here we studied the optimal conditions for oocyte collection by induction of superovulation, and the development of embryos after cryopreservation in F344 rats. The response to pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) was examined by injection of 150 IU/kg PMSG + 75 IU/kg hCG or 300 IU/kg PMSG + 300 IU/kg hCG. Superovulation was achieved at high efficiency by an injection of 150 IU/kg PMSG + 75 IU/kg hCG. Furthermore, superovulation in this strain showed similar high response as Wistar rats. Of 2-cell embryos cryopreserved by vitrification in a solution containing 10% propylene glycol, 30% ethylene glycol, 20% Percoll and 0.3 M sucrose, more than 90% survived after warming and 32% developed to offspring. However, the freezability of pronuclear stage embryos was extremely low. This study demonstrated that sufficient unfertilized oocytes and embryos can be collected from F344 rats by the induction of superovulation with 150 IU/kg PMSG + 75 IU/kg hCG. Furthermore, cryopreservation of 2-cell embryos using this vitrification protocol can now be applied to maintaining valuable rat strains derived from the F344 inbred strain as genetic resources.     

Senescent terminal weight loss in the male F344 rat

Loss of weight, often of unknown cause and culminating in death, commonly occurs in humans at advanced ages. Rats that live to old ages, such as the Fischer 344 (F344) strain, also exhibit a terminal loss in body weight. A presently held hypothesis is that the terminal weight loss in the F344 rat model is due to reduced food intake because of an alteration in hypothalamic function resulting in early satiation. We report findings on terminal weight loss and food intake in male F344 rats fed ad libitum (AL group) or a life-prolonging dietary regimen in which caloric intake was restricted (DR group). Rats in both dietary groups that did not exhibit a terminal weight loss died at younger ages than those exhibiting the loss. Terminal weight loss in the AL group was not associated with decreased food intake; indeed, half of the rats in this group had an increased food intake during the period of terminal weight loss. This finding is not in accord with the presently held hypothesis. In the DR group, terminal weight loss was associated with reduced food intake. Pathology (renal disease and neoplasms) did not explain the presence or absence of the association between reduced food intake and weight loss in either dietary group. The duration of the period of terminal weight loss was similar for the AL and DR groups. Apparently, restricting calories delays the occurrence but does not affect the duration of senescent terminal weight loss.     

肌注和药饵给药下诺氟沙星在南美白对虾血淋巴中药代动力学

本文分析了盐度1‰和15‰下诺氟沙星肌肉注射给药(剂量10mg/kg)和盐度15‰下药饵口服给药(剂量15mg/kg和30mg/kg)后南美白对虾血淋巴中药代动力学。在盐度1‰和15‰下,南美白对虾肌注给药后血药浓度的变化趋势基本相似,血药浓度与时间关系曲线适合用二室模型来描述,其药动学方程分别为C0=35.422×e-9.778t 4.363×e-0.165t和C0=35.144×e-13.335t 7.888×e-0.608t,但两盐度下部分药动学参数差别较大。药饵口服给药时,给药剂量与血药浓度未呈明显的正相关,且血药浓度—时间关系曲线均表现出双峰现象。以30mg/kg剂量药饵口服给药后,药峰出现的时间分别为给药后4h和12h,峰浓度分别为2.86μg/mL和2.04μg/mL;以15mg/kg剂量给药时也得到相似的双峰现象,但第二峰浓度出现的时间为8h。     

Pharmacokinetics of phenoxodiol, a novel isoflavone, following intravenous administration to patients with advanced cancer

Background  

Phenoxodiol is a novel isoflavone currently being studied in clinical trials for the treatment of cancer. This study reports the pharmacokinetics of phenoxodiol in patients with cancer.     

Histamine pharmacokinetics in tumor and host tissues after bolus-dose administration in the rat

In this study, we estimated interstitial histamine concentrations in normal and malignant tissues after a single intravenous (i.v.) injection of 0.5 mg/kg histamine dihydrochloride in the rat. The microdialysis technique was used to collect interstitial fluid from subcutis, liver and a NGW adenocarcinoma. Histamine was absorbed with equal efficiency to all tissues (t 1/2 AB 3.9-7.7 minutes) but maximum concentration (Cmax; nmol/l) of histamine was higher in liver (2,388 +/- 357) than in subcutis (951 +/- 125) (p < 0.01) and subcutaneous tumor (523 +/- 140) (p = 0.01) and, moreover, Cmax in liver tumor (1,752 +/- 326) was higher than in subcutaneous tumor (p = 0.01). The tl/2 elimination was significantly longer in subcutis and subcutaneous tumor than in liver and liver tumor. Area under the curve (AUC; mmol-min/l) for histamine was significantly lower in subcutaneous tumor (9.8 +/- 2.3) than in liver (17.6 +/- 1.9) (p = 0.03) and liver tumor (15.8 +/- 1.8) (p = 0.03). Local tissue blood flow as assessed by the 14C-ethanol method was not significantly altered by the histamine administration. In conclusion, after an i.v. injection of histamine dihydrochloride a higher maximum concentration and AUC of histamine was reached in liver and liver tumor than in subcutaneous tissues.     

Pharmacokinetics of ipriflavone, an isoflavone derivative, after intravenous and oral administration to rats hepatic and intestinal first-pass effects

Pharmacokinetic parameters of ipriflavone were evaluated after intravenous administration of spray-dried ipriflavone with polyvinylpyrrolidone, SIP (5, 10, 20, and 40 mg/kg as ipriflavone) and oral administration of SIP (50, 100, and 200 mg/kg as ipriflavone) to rats. The hepatic, gastric, and intestinal first-pass effects of ipriflavone were also measured after intravenous, intraportal, intraduodenal, and oral administration of SIP (20 or 50 mg/kg as ipriflavone) to rats. After intravenous and oral administration, the pharmacokinetic parameters of ipriflavone were dose-independent. The extent of absolute oral bioavailability (F) was also independent of oral doses; the mean F value was approximately 24%. Considering the amount of unchanged ipriflavone recovered from 24-hr gastrointestinal tract (the mean value was approximately 12%), the low F values could be due to the hepatic, gastric, and/or intestinal first-pass effects. Based on total body clearance (CL) data of ipriflavone after intravenous administration, the first-pass effect in the heart and lung could be almost negligible, if any, in rats. Approximately 30% of ipriflavone absorbed into the portal vein was eliminated by liver (hepatic first-pass effect) based on intravenous and intraportal administration of SIP. The area under the plasma concentration-time curve from time zero to time infinity (AUC) values after oral administration and intraduodenal instillation of SIP, 50 mg/kg as ipriflavone, were not significantly different, but the values were significantly smaller (129 and 116 microg ml/min) than that after intraportal administration of SIP, 20 mg/kg as ipriflavone (513 microg ml/min based on 50 mg/kg), indicating that gastric first-pass effect of ipriflavone was negligible, but intestinal first-pass effect was considerable in rats. Therefore, the low F value of ipriflavone after oral administration to rats was mainly due to intestinal first-pass effect. The hepatic first-pass effect and incomplete absorption of ipriflavone from rat gastrointestinal tract could also contributed to the low F in rats.     

Orchiectomized Fischer 344 male rat models body composition in hypogonadal state

The hypogonadal state in men is accompanied by substantial decreases in muscle and bone mass and by an increase in adiposity. Most of the strains of orchiectomized (ORX) rat that have been used to model this state display substantial losses in bone, but only subtle changes in adiposity and muscle mass. In order to identify a rat model displaying a robust catabolic response to ORX, we studied three strains: Fischer 344 (F344), Brown Norway and Wistar. ORX caused a significant and sustained decrease in weight gained by F344, but only a trend toward reduced weight gain in Brown Norway rats and a modest reduction weight gain in Wistar rats that was significant only after 56days. ORX suppressed food intake in F344 rats, and to a lesser degree in Brown Norway and Wistar rats. ORX reduced muscle mass significantly in F344 rats, but not in Brown Norway or Wistar rats. ORX increased adiposity moderately in F344 rats and substantially in Wistar rats. ORX caused a marked reduction in prostate mass and increase in bone resorption in all three strains. Thus, F344 was the only strain in which ORX produced substantial decreases in food intake, body weight and muscle mass with increased adiposity and increased bone resorption. We conclude that the F344 rat displays a broad range of catabolic effects following ORX and is the best rat model for studying the androgenic pathway and strategies for reversing catabolic changes induced by hypogonadism.