Tumor-targeting intravenous lipid emulsion of paclitaxel:Characteristics,stability,toxicity,and toxicokinetics / 药物分析学报

Lipid nanoemulsions are promising nanodrug delivery carriers that can improve the efficacy and safety of paclitaxel(PTX).However,no intravenous lipid emulsion of PTX has been approved for clinical treatment,and systemic safety profiles have not yet been reported.Here we outline the development of a PTX-loaded tumor-targeting intravenous lipid emulsion(PTX Emul)and describe its characteristics,colloidal stability,and systemic safety profiles in terms of acute toxicity,long-term toxicity,and tox-icokinetics.We also compare PTX Emul with conventional PTX injection.Results showed that PTX Emul exhibited an ideal average particle size(approximately 160 nm)with narrow size distribution and robust colloidal stability under different conditions.Hypersensitivity reaction and hemolysis tests revealed that PTX Emul did not induce hypersensitivity reactions and had no hemolytic potential.In addition,where the alleviated systemic toxicity of PTX Emul may be attributed to the altered toxicokinetic characteristics in beagle dogs,including the decreased AUC and increased plasma clearance and volume of distribution,PTX Emul alleviated acute and long-term toxicity as evidenced by the enhanced the median lethal dose and approximate lethal dose,moderate body weight change,decreased bone marrow suppression and organ toxicity compared with those under PTX injection at the same dose.A fundamental understanding of the systemic safety profiles,high tumor-targeting efficiency,and superior antitumor activity in vivo of PTX Emul can provide powerful evidence of its therapeutic potential as a future treatment for breast cancer.

In Vitro and In Vivo evaluation of montmorillonite for paraquat poisoning

Abstract Evaluation of montmorillonite for paraquat by in vitro and in vivo test. In vitro test were evaluated by a batch test, taking the paraquat concentration, adsorbents, reaction environment and time as indices, the absorption rate was screened by orthogonal design. In vivo test was executed with rabbits. Group 1: 4 rabbits dosed with montmorillonite. Group 2: 8 rabbits dosed with 200 mg/kg paraquat. Group 3: 6 rabbits dosed with 200 mg/kg paraquat then gavage with montmorillonite 5 min later. Group 4: 6 rabbits dosed with 200 mg/kg paraquat then gavage with montmorillonite 30 min later. Blood paraquat concentration, serum cytokines, blood gas analysis and histopathology of lung were implemented. In vitro test found that all the four factors influence the absorption rate of paraquat (P < 0.05). In vitro test found that oral montmorillonite could change toxicokinetics parameters of paraquat (P < 0.05); decrease raised serum TGF-ß1 and HMGB1 (P < 0.05) and alleviate the histopathology damage of lung. Montmorillonite might exert its protective effects on paraquat induced damage

Toxicokinetics of Vitexin Injection in Beagle Dogs / 中国药学杂志

OBJECTIVEP: To investigate the toxicokinetic and tissue distribution of vitexin in Beagle dogs. METHODS: Beagle dogs were randomly divided into three groups, and received vitexin injection at small, medium and big doses of 50, 20 and 8 mg•kg-1. They were given medicine once a day for consecutive 3 months by intravenous drip. The blood samples of Beagle dogs were drawn at different time points on the first and last day of administration, and concentrations in plasma were detected by HPLC method. RESULTS: Intravenous drip the vitexin injection at the doses of 8, 20 and 50 mg•kg-1, the blood concentration of vitexin linearly metabolized in Beagle dogs when given medicine for 1, 22, 44 and 83 d. Vitexin was significantly accumulated in Beagle dogs, and the accumulation was disappeared, and the exposure decreased with the prolonged time at the dose of 50 mg•kg-1; at the dose of 8 and 20 mg•kg-1, vitexin did not accumulate in Beagle dogs, and the exposure decreased with prolonged administration time. CONCLUSION: There is no accumulation of repeated drug delivery in the Beagle dog's body by intravenous drip at the doses of 8 and 20 mg•kg-1.

Intoxicaciones agudas por medicamentos consumidos con fines de abuso / Acute poisoning due to medications used for abuse purposes

Introducción: El consumo de sustancias con fines de abuso y entre ellas los medicamentos, se ha incrementado a nivel mundial. Objetivo: Caracterizar a los pacientes atendidos por intoxicaciones agudas debido a medicamentos consumidos con fines de abuso. Métodos: El universo estuvo constituido por consultas de 961 pacientes, realizadas al servicio de información toxicológica de urgencia del Centro Nacional de Toxicología, durante el período 2010 al 2014. Fueron todas las intoxicaciones agudas por consumo de sustancias con fines de abuso. La serie incluyó 578 pacientes con intoxicaciones agudas con fines de abuso, donde el agente causal fueron los medicamentos. Se recopilaron los datos sociales y biológicos, formas de consumo, grupos farmacológicos, manifestaciones clínicas, aspectos de la toxicocinética y la toxicodinamia. Resultados: Los consumidores de medicamentos con fines de abuso, representaron el 60,14 por ciento de las consultas por consumo de sustancias con fines de abuso. El grupo etario de hasta 20 años fue el de mayor consumo (360 consultas; 62,28 por ciento) y el sexo masculino el más frecuente (447 pacientes; 77,3 por ciento). La combinación de medicamentos más alcohol fue la forma de consumo más empleada (292 consultas; 50,5 por ciento). La carbamazepina fue el medicamento más consumido (305 consultas; 52,7 por ciento). Conclusiones: Predominó la intoxicación aguda en el grupo etario de 10-20 años y del sexo masculino. La ingestión de medicamentos más alcohol, fue la forma de consumo más empleada. El grupo farmacológico más utilizado con fines no médicos, fue el de los anticonvulsivantes (carbamazepina), seguido de las benzodiacepinas y los opiáceos. Las manifestaciones clínicas que predominaron fueron del sistema neurológico, seguido del cardiovascular y el digestivo(AU)

ABSTRACT Introduction: The consumption of substances for the purpose of abuse, including drugs, has increased worldwide. Objective: To characterize patients treated for acute intoxications due to drugs consumed for abuse purposes. Methods: The universe was constituted by consultations of 961 patients, made to the emergency toxicology information service of the National Center of Toxicology, during the period from 2010 to 2014. They were all acute intoxications due to the consumption of substances for the purpose of abuse. The series included 578 patients with acute intoxications for abuse, where the causative agent was medication. We collected social and biological data, forms of consumption, pharmacological groups, clinical manifestations, aspects of toxicokinetics and toxicodynamics. Results: Consumers of medications for the purpose of abuse accounted for 60.14 percent of consultations for the consumption of substances for the purpose of abuse. The age group of up to 20 years consumed the most (360 consultations, 62.28 percent) and the most frequent was the male sex (447 patients, 77.3 percent). The combination of drugs plus alcohol was the most used form of consumption (292 consultations, 50.5 percent). Carbamazepine was the most commonly used medication (305 consultations, 52.7 percent). Conclusions: Acute intoxication predominated in the age group of 10-20 years and of the male sex. The ingestion of drugs plus alcohol was the most used form of consumption. The most used pharmacological group for non-medical purposes was the anticonvulsant group (carbamazepine), followed by benzodiazepines and opiates. The clinical manifestations that predominated were of the neurological system, followed by cardiovascular and digestive(AU)

Determination of voriconazole in dog plasma by lc-ms/ms and its toxicokinetics / 中国药学杂志

OBJECTIVE: To establish a method for the determination of voriconazole in dog plasma and investigate its toxicokinetics. METHODS: After protein precipitation with acetonitrile, voriconazole and fluconazole were separated on an Agilent Poroshell120 EC-C18 column (2.1 mm×50 mm, 2.7 μm), with acetonitrile and water (0.1% FA) as the mobile phase at a flow rate of 0.3 mL·min-1. Detection was carried out by the electrospray positive ionization mass spectrometry in the multiple reacion monitoring (MRM) mode. The MRM transitions of m/z 335.1→281.3 and m/z 307.1→220.0 were used to quantify voriconazole and fluconazole, respectively. Thirty Beagle dogs received intravenous infusion of voriconazole at low, medium and high doses (1, 3, 6 mg·kg-1·d-1) once a day for 12 weeks. RESULTS: The calibration curve was linear over 10-10 000 ng·mL-1 . RSD was less than 15%, and the accuracy was within the range of 85%-115%.The exposure of voriconazole to females was significantly higher than that of males in Beagle dogs. When the dose was 1-6 mg·kg-1·d-1, the exposure of voriconazole to beagle dogs increased with the increase of dose, and the drug did not accumulate. CONCLUSION: The method can be applied to the determination of voriconazole in dog plasma, and is suitable to the toxicokinetics study of voriconazole.

Embryo-fetal development toxicity of carenoprazan hydrochloride / 中国药科大学学报

@#Carenoprazan has the similar structure and mechanism with the potassium-competitive blocker vonoprazan. Howerver, its safety during the pregnancy remains uncertain. To study the embryo-fetal development toxicity and toxicokinetics of carenoprazan hydrochloride via oral administration, time-mated Sprague-Dawley rats were divided into 5 groups, treated with normal saline, cyclophosphamide for injection(3. 8 mg/kg), and carenoprazan hydrochloride(20, 60, 200 mg/kg), respectively. Administrated orally from gestation day(GD)6 - 15. At the termination(GD 20), pregnant dams were sacrificed, and concentrations of carenoprazan hydrochloride as well as its metabolite in plasma and issues of both maternal and fetus were examined. As a result, the body weight gain of maternal in both high(200 mg/kg)and medium(60 mg/kg)dose as well as the food consumption of high-dose were decreased during GD 10-16. At the high dose group, decrease of crown rump length of fetuses were significant. Also, skeletal malformation/variations of fetus increased obviously at both high- and medium- dosage. The toxcicokinetics of carenoprazan hydrochloride are linear after single treatment between 20-200 mg/kg. The placental barrier was penetrated by carenoprazan hydrochloride and metabolite, and the distribution of metabolite in organs were similar in both maternal and fetus, with the highest concentration in livers. Therefore might resulted in the development toxicity. The No Observed Adverse Effect Level(NOAEL)of carenoprazan hydrochloride for both maternal and fetal was 20 mg/kg.

Long-circulating and target-specific distributions of cyanine 5.5-labeled hyaluronic acid nanoparticles in mouse organs during 28 days after a single administration / 대한수의학회지

Although hyaluronic acid (HA) has been developed as a nanoparticle (NP; 320–400 nm) for a drug delivery system, the tissue targeting efficacy and the pharmacokinetics of HA-NPs are not yet fully understood. After a dose of 5 mg/kg of cyanine 5.5-labeled HA-NPs or HA-polymers was intravenously administrated into mice, the fluorescence was measured from 0.5 h to 28 days. The HA-NPs fluorescence was generally stronger than that of HA-polymers, which was maintained at a high level over 7 days in vivo, after which it gradually decreased. Upon ex vivo imaging, liver, spleen, kidney, lung, testis and sublingual gland fluorescences were much higher than that of other organs. The fluorescence of HA-NPs in the liver, spleen and kidney was highest at 30 min, where it was generally maintained until 4 h, while it drastically decreased at 1 day. However, the fluorescence in the liver and spleen increased sharply at 7 days relative to 3 days, then decreased drastically at 14 days. Conversely, the fluorescence of HA-polymers in the lymph node was higher than that of HA-NPs. The results presented herein may have important clinical implications regarding the safety of as self-assembled HA-NPs, which can be widely used in biomedical applications.

Toxicokinetics of Ginkgolide B Injection in Beagle dogs / 医药导报

Objective To investigate the toxicokinetic properties of ginkgolide B(GB) injection after single or repeat-ed administration by intravenous drip in Beagle dogs and to provide evidence for its rational use. Methods Beagle dogs were randomly divided into three groups,and received GB injection at big,medium and small doses of 80,20 and 5 mg·kg-1, re-spectively,by iv drip for 30 min per day and for 6 consecutive days per week for up to 91 days.The blood samples of Beagle dogs were drawn at different time points on the first and last day of administration,and concentrations in plasma were detected by GC-MS method.Toxicokinetic parameters were calculated by DAS pharmacokinetic software and statistically analyzed by SPSS 11.5 software. Results The elimination half-life (t1/2β) of GB at single dose of 5,20,80 mg·kg-1were(110.2±32.6),(115.4± 12.8),(98.6±26.8) min, respectively.The AUC0-twere (61.1±7.4), (348.6±90.5), (2 046.2±356.4) mg·L-1·min,re-spectively.The t1/2βof GB at mutiple doses of 5,20,80 mg·kg-1on the 91rd day were (117.9±28.0),(118.2±17.0),(120.5± 49.4) min,respectively.The AUC0-twere (67.9±14.9), (218.3±31.8), (1 986.4±426.6) mg·L-1·min, respectively.There was no significant difference in main toxicokinetic parameters including t1/2βamong the single or repeated dosage groups, but AUC0-tand Cmaxincreased proportionally with doses. Conclusion The curves of single and repeated intravenous drip of GB in-jection in beagle dogs were in line with the two atrioventricular model,with linear dynamic characteristics and there was no accu-mulation of repeated drug delivery in the body.

Absorption, distribution and excretion of 2-fluorine-6-trifl-uoromethylpyridine in rats by radioactivity isotope tracing method / 中国药理学与毒理学杂志

OBJECTIVE To study the absorption,distribution and excretion of 2-fluorine-6-trifluoromethylpyridine (JJBD) in rats.METHODS [14C] Radioactivity isotope tracing method was used.Male SD rats were ig given a single dose of JJBD 10 and 100 mg·kg-1 (radioactivity:3.7 GBq·kg-1).Concentrations of rat plasma,tissue,feces,urine and bile were determined with a liquid scintillation counting (LSC) analyzer.Toxicokinetics (TK) parameters were fitted using WinNonlin.RESULTS TK parameters of JJBD 10 and 100 mg · kg-1 in male SD rats were as follows:area under the curve (AUC（0-t）) was 22 548±1579 and (203 395±27 586) h·iμg Eq.·L-1,half time (t1/2) was 15.8±1.0 and (14.1±0.9) h,peak time (Tmax) was 4.0±3.0 and (6.0±5.0) h,peak concentration (Cmax) was 1450±355 and (7776±1703) μg Eq.·L-1.JJBD was mainly distributed in fat,livers,kidneys,stomachs and intestinal walls.The concentration of JJBD in most of the tissues reached peak values after 4 h.However,JJBD couldn't be detected in the muscle,thymus gland,brain,gonad or spleen.Excretion rate of JJBD was 43.1％ in urine,29.7％ in feces and 9.97％ in cleaning solution within 0-168 h.JJBD could be excreted through bile at a rate of 28.1％ within 0-72 h.CONCLUSION JJBD can be absorbed immediately and excreted slowly in SD rat.There is no accumulation risk.The distribution of JJBD in vivo is very extensive,but cannot go through the blood-brain barrier.JJBD is mostly excreted through feces and urine.

Determination of (S)-Pantoprazole Sodium in Dog Plasma by LC-MS/MS and Its Toxicokinetic Study / 中国药学杂志

OBJECTIVE: To establish an LC-MS/MS method to determine (S)-pantoprazole sodium in dog plasma and investigate its toxicokinetics. METHODS: After protein precipitation with acetonitrile, the analyte and internal standard were separated on CHIRALCEL OJ-RH column (4.6 mm ×150 mm, 5 μm) with acetonitrile-water (28∶72) as mobile phase eluted at a flow rate of 0.6 mL·min-1. Detection was carried out by electrospray positive ionization mass spectrometry in the multiple reaction monitoring (MRM) mode. The MRM transitions of m/z 384.0/199.8 and m/z 180.0/110.0 were used to quantify (S)-pantoprazole sodium and phenacetin, respectively. Beagle dogs were intravenously given (S)-pantoprazole sodium for 4 weeks at low, medium, and high dosages (10, 20, 40 mg·kg-1·d-1). RESULTS: The calibration curve was linear over the concentration range of 50-30 000 ng·mL-1. The RSDs were less than 15%, and the accuracy was in the range of 85%-115%. The AUC0-4 h and ρmax of (S)-pantoprazole sodium were proportional to the dosages. CONCLUSION: The established method can be applied to the determination of (S)-pantoprazole sodium in plasma of dogs and is suitable for the toxicokinetic study.

LC-Ms/Ms method developed for determination of albiflorin in rat plasma and its application on toxicokinetic study / 国际药学研究杂志

Objective To develop and validate a LC-MS/MS method for the determination of albiflorin in rat plasma. Methods Plasma samples were extracted by liquid-liquid extraction with a mixture of ethyl acetate-isopropanol (95:5, V/V) to prepare samples for analysis. Chromatographic separation was performed on a Poroshell 120 EC-C18 column (50 mm× 2.1 mm I.D. 2.7 µm). The mobile phase consisted of acetonitrile-water followed gradient elution. Detection of albiflorin and the internal standard (IS) lacosamide was achieved by ESI MS/MS in the positive ion mode using m/z 498.5→m/z 197.1 and m/z 251.3→m/z 108.2 transitions, respectively. Results The method was linear in the range of 20 to 2000 ng/ml when 50 µl plasma was analyzed. The lower limit of quantification was 20 ng/ml. The inter- and intra-day precision values were both below 15%, and the accuracy (relative error) was within ±8.06% in all quality control samples. Conclusion The method provides a sensitive and rapid means for the determination of albiflorin in rat plasma, and completely meets the requirements for toxicokinetic study.

LC-MS/MS method developed for determination of albiflorin in rat plasma and its application on toxicokinetic study / 国际药学研究杂志

Objective To develop and validate a LC-MS/MS method for the determination of albiflorin in rat plasma. Meth?ods Plasma samples were extracted by liquid-liquid extraction with a mixture of ethyl acetate-isopropanol(95:5,V/V)to prepare samples for analysis. Chromatographic separation was performed on a Poroshell 120 EC-C18 column(50 mm × 2.1 mm I.D. 2.7μm). The mobile phase consisted of acetonitrile-water followed gradient elution. Detection of albiflorin and the internal standard(IS)lacos?amide was achieved by ESI MS/MS in the positive ion mode using m/z 498.5→m/z 197.1 and m/z 251.3→m/z 108.2 transitions,respec?tively. Results The method was linear in the range of 20 to 2000 ng/ml when 50μl plasma was analyzed. The lower limit of quantifi?cation was 20 ng/ml. The inter-and intra-day precision values were both below 15%,and the accuracy(relative error)was within ± 8.06%in all quality control samples. Conclusion The method provides a sensitive and rapid means for the determination of albiflorin in rat plasma,and completely meets the requirements for toxicokinetic study.

Toxicological characteristics of Ochratoxin A and its impact on male reproduction / 中华男科学杂志

Ochratoxin A (OTA) is found not only nephrotoxic, teratogenic, neurotoxic, and immunotoxic, but also reprotoxic for human and animals. In the recent decade, more attention has been paid to the impact of OTA on human reproduction and the studies of its underlying mechanisms. Many studies show that OTA affects the function of the reproductive system by acting as an endocrine disrupter and, as a testicular toxin, decreases sperm quality and even induces testis cancer. This review summarizes the toxicological characteristics and toxicokinetic process of OTA as well as recent progress in the studies of various toxic effects of OTA and their underlying mechanisms, hoping to call the attention from more people to the toxicity of OTA to male reproductive health.

Low-Dose Bisphenol A Increases Bile Duct Proliferation in Juvenile Rats: A Possible Evidence for Risk of Liver Cancer in the Exposed Population?

Increasing concern is being given to the association between risk of cancer and exposure to low-dose bisphenol A (BPA), especially in young-aged population. In this study, we investigated the effects of repeated oral treatment of low to high dose BPA in juvenile Sprague-Dawley rats. Exposing juvenile rats to BPA (0, 0.5, 5, 50, and 250 mg/kg oral gavage) from post-natal day 9 for 90 days resulted in higher food intakes and increased body weights in biphasic dose-effect relationship. Male mammary glands were atrophied at high dose, which coincided with sexual pre-maturation of females. Notably, proliferative changes with altered cell foci and focal inflammation were observed around bile ducts in the liver of all BPA-dosed groups in males, which achieved statistical significance from 0.5 mg/kg (ANOVA, Dunnett’s test, p<0.05). Toxicokinetic analysis revealed that systemic exposure to BPA was greater at early age (e.g., 210-fold in C(max), and 26-fold in AUC at 50 mg/kg in male on day 1 over day 90) and in females (e.g., 4-fold in C(max) and 1.6-fold in AUC at 50 mg/kg vs. male on day 1), which might have stemmed from either age- or gender-dependent differences in metabolic capacity. These results may serve as evidence for the association between risk of cancer and exposure to low-dose BPA, especially in young children, as well as for varying toxicity of xenobiotics in different age and gender groups.

Efectos nocivos del plomo para la salud del hombre / Harmful effects of lead on human health

El plomo es un metal pesado que se encuentra de forma natural en la corteza terrestre y ha sido distribuido en el ambiente, debido a fuentes fijas o móviles contaminantes antropogénica o naturales. Existen compuestos orgánicos e inorgánicos del plomo, que son liberados al aire durante la combustión del carbono y aceite. Este puede ingresar al organismo por tres vías: respiratoria, digestiva y dérmica o cutánea y causar efectos nocivos para la salud del hombre a nivel celular, sin que ni siquiera puedan ser percibidos a corto plazo. El objetivo de la revisión fue exponer las características del plomo y su influencia para la salud de la población. Dados los efectos nocivos del plomo y su influencia para la salud de la población, este es en la actualidad, un motivo de atención especial por constituir una parte importante de la contaminación ambiental presente en muchas ciudades en el mundo.

Lead is a heavy metal found in its natural form in Earth's crust, and distributed in the environment by anthropogenic or natural, fixed or mobile sources of pollutants. Organic and inorganic lead compounds are released to the air during carbon and oil combustion. Lead may enter the human body by three routes: respiratory, digestive, or dermal or cutaneous, but its damaging effects on human health at cell level can not be noticed in the short term. The purpose of the review was to characterize lead and determine its influence on the health of the population. Special attention is currently being given to this subject, due to the harmful effects of lead and its influence on the health of the population, and because lead constitutes a large part of the environmental pollution present in many cities worldwide.

Thirty years of research on toxicant metabolism and toxicokinetics in China / 中国药理学与毒理学杂志

Toxicant metabolism and toxicokinetics are an integrated part of toxicology. They study the absorption,targeted distribution,metabolic detoxicification or bioactivation,excretion and elimination of toxic substances after the body′s exposure via different routes,and also evaluate the effects of various factors on the disposition of poisons. The results of the studies provide essential data on the relation?ships between exposure kinetics and toxicological effect and their mechanisms. They also help to find possible targets of intoxication or detoxicification pathways,which can lead to efficient countermea?sures. In this review,the author summarized the thirty years of progress and features of the research on toxicant metabolism and toxicokinetics in China.

A physiologically based toxicokinetics and toxicodynamics model in rats following both oral and subcutaneous exposure to chlorpyrifos / 中国药理学与毒理学杂志

OBJECTIVE To develop and validate a physiologically based toxicokinetics and toxico?dynamics(PBTK/TD)model for chlorpyrifos(CPF)in rats following both oral and subcutaneous expo?sures to CPF. METHODS ①A PBTK/TD model was established with toxicokinetics and toxicodynam?ics data in literature,which was used for predicting contents of CPF and 3,5,6-trichloro-2-pyridinol (TCP)in blood and activities of acetylcholine esterase(AChE)in the plasma and brain of rats exposed to CPF.②Rats were given 50 mg · kg-1 CPF oral and 50 mg · kg-1 CPF sc simultaneously. Blood and brain samples were collected at 0,1,2,4,6,8,12,24 and 48 h,respectively,after CPF administration (n=5). CPF And TCP contents in plasma,activities of AChE in the plasma and brain were deter?mined,and compared with the simulation values by PBTK/TD model in order to validate the accuracy of the model. RESULTS It was predicted by the PBTK/TD model that after the administration (oral+sc) of CPF 20+20,10+30 and (30+10)mg · kg-1,the concentrations of CPF and TCP in plasma increased and then decreased with time in each group. The inhibitory level of AChE activity in the plasma was orally dose-dependent,while AChE activity of the brain was more sensitive to CPF subcutaneous exposure. The simulation values obtained by the PBTK/TD model were not significantly different from the experimental values obtained by co-administered CPF at(50+50)mg · kg-1. CONCLUSION This CPF PBTK/TD model can quantitatively estimate target tissue dosimetry and AChE inhibition.

Toxicokinetics of paraquat in Korean patients with acute poisoning

To conduct a kinetic study of paraquat (PQ), we investigated 9 patients with acute PQ intoxication. All of them ingested more than 20 ml of undiluted PQ herbicide to commit suicide and arrived at our hospital early, not later than 7 h after PQ ingestion. The urine dithionite test for PQ in all of the nine patients was strongly positive at emergency room. Blood samples were obtained every 30 min for the first 2~3 h and then every 1 or 2 h, as long as the clinical progression was stable among the patients for 30 h after PQ ingestion. The area under the plasma concentration-time curve (AUCinf), which was extrapolated to infinity, was calculated using the trapezoidal rule. Toxicokinetic parameters, such as the terminal elimination half-life, apparent oral clearance, and apparent volume of distribution (Vd/F) were calculated. The maximum PQ concentration (Cmax) and the time to reach maximum PQ concentration (Tmax) were also obtained. Plasma PQ concentrations in nine patients were well described by a bi-exponential curve with a mean terminal elimination half-life of 13.1+/-6.8 h. Cmax and AUCinf were 20.8+/-25.7 mg/l and 172.5+/-160.3 h.mg/l, respectively. Apparent volume of distribution and apparent oral clearance were 50.9+/-61.3 l/kg and 173.4+/-111.2 l/h, respectively. There were a significant correlation (r =0.84; p<0.05) between the PQ amount ingested and Cmax. AUCinf also showed a significant correlation (r =0.83; p<0.05) with the PQ amount ingested. These correlations provide evidence that PQ has dose-linear toxicokinetic characteristics.

Detection of Metabolites of Vecuronium Bromide in Visceral Samples Solves A Typical Death Mystery- (Toxicokinetics- Studies Using Gc-Ms Technique).

Introduction: On Sudden death of a medical student (20 year old girl) of National Institute of Medical Science autopsy materials along with site of injection were sent to F.S.L. It was informed during investigation that the girl took tetanus vaccine before death. In crime scene investigation Forensic Team observed that it was a case of gross negligence of dispensing wrong injection. Material: Tests were performed on viscera material viz., liver, spleen, kidney, lungs, brain, skin and blood etc. Mystery of suspected death was solved when a new GC-MS application was designed to get the unknown drug and various fragments of extracted material were studied. Method: A new method was developed on gas-chromatography-mass spectrophotometer and TL.C using various solvent systems is explained. Results: Metabolite fragments of vecuronium bromide a muscle relaxant were surprisingly observed in Viscera material, Blood sample and Skin piece from Leftt cubital fossa from this young girl, whose death is questioned. Conclusion: Structural elucidations of fragments provide a new approach to toxicokinetics. Th e explanation of fragments obtained were structurally compared with other neuromuscular blocking groups like atracurium and succinyl choline Th e presence of bromide attached cholest-5-en-Br, hydroxylated cholest-5-en-ol as hydroxylated product, acetylated fragments as cholest-5-enacetate and piperidone-2-one present in visceral samples indicates structural part obtained from vecuronium bromide drug. Th ese metabolites studies makes the case studies highly informative. Beside this new method of extractions, TLC systems and colouring reagents are also explained.

Toxicokinetics of norcantharidin lipid microsphere for injection in Beagle's dog following 90 d repeated iv administration / 中草药

Objective: To evaluate the toxicokinetics and in vivo accumulation of norcantharidin lipid microsphere for injection (NCTD-LM) in Beagle's dogs following 90 d repeated iv administration by comparing with sodium demethylcantharidate injection (NCTD-I). Methods: An ultra high performance liquid chromatography-tandem mass spectrum method was employed to determine the NCTD in plasma of Beagle's dog after 1, 44, and 90 d repeated iv administration. The toxicokinetic parameters were calculated from the plasma concentration. Results: After the first iv administration of 0.8, 1.6, and 3.2 mg/kg NCTD-LM to Beagle's dog, the AUC0-t were (2.22 ± 0.53), (4.77 ± 1.13), and (13.43 ± 3.64) h∙mg/L, respectively, while the t1/2 were (1.37 ± 0.18), (1.64 ± 0.42), and (1.98 ± 0.25) h, respectively. After the 90 d repeated iv administration of 0.8, 1.6 and 3.2 mg/kg NCTD-LM to Beagle's dog, the AUC0-t were (3.58 ± 0.95), (11.4 ± 2.0), and (23.5 ± 3.9) h·mg/L, respectively, while the t1/2 were (3.87 ± 1.90), (5.75 ± 3.29), and (5.84 ± 2.45) h, respectively. For NCTD-I, the AUC0-t were (9.07 ± 2.09) and (14.1 ± 3.0) h∙mg/L respectively after 1 and 90 d repeated iv administration, while the t1/2 were (2.84 ± 1.34) and (3.53 ± 1.26) h. 15 and 30 d after the end of administration, the concentration of NCTD in plasma of Beagle's dog in each group were all dropped below the lowest limit of quantification (LLOQ). Conclusion: NCTD displays a nonlinear elimination at the dose range of 0.8-3.2 mg/kg after iv administration of NCTD-LM to Beagle's dog. Over the 90 d repeated iv administration period, the plasma concentration levels, AUC0-t, and t1/2 for both NCTD-LM and NCTD-I are increased with time increasing. However, no accumulation of NCTD is observed for the both formulations.