The major metabolite formed via the cytochrome P450 pathway is glycidamide. Species differences in the formation of this metabolite have been observed, with acrylamide converted to glycidamide to a greater extent in the mouse than in the rat, based on urinary metabolites.
When acrylamide was administered to rats, the conversion to glycidamide was 51% following the administration of 5 mg/kg and decreased to 13% after 100 mg/kg, based on the measurement of hemoglobin adducts. The conversion of acrylamide to glycidamide was higher following subchronic dosing as well. Acrylamide hemoglobin adduct formation was approximately 2- or 4.5-fold greater for oral (20 mg/kg/day for 15, 21, 34 or 47 days) or intraperitoneal (50 mg/kg/day for 11 days) dosing, respectively, than glycidamide adduct formation. Oral administration resulted in approximately 30% fewer acrylamide adducts than intraperitoneal dosing; however, more glycidamide adducts were formed after oral dosing. The authors suggested that the reason for these differences was due to a higher conversion of acrylamide to glycidamide following oral dosing, when compared with intraperitoneal dosing.
The conversion of acrylamide to glycidamide is saturable, ranging from 50% at very low doses to 13% at 100 mg/kg bw in treated rats. Both agents are detoxified by glutathione conjugation, and glycidamide is also detoxified by hydrolysis. Both agents react directly with hemoglobin in vivo, but DNA adducts result only from the formation of glycidamide.
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
解毒与急救
/SRP:/ 高级治疗：对于无意识、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸林格氏液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。使用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。 /Poisons A and B/
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
/HUMAN EXPOSURE STUDIES/ ln a study in China, hemoglobin (Hb) adducts of acrylamide and glycidamide were determined in 41 workers who were exposed to acrylamide for periods ranging between one month and 11.5 years and who had concurrent medical and neurological examinations. The levels of N-terminal valine adducts of acrylamide ranged from 0.3 to 34 nmol/g Hb, with directly proportional formation of glycidamide adducts to the same residue in Hb. Background levels of valine adducts in Hb were not found in a group of 10 controls, with one possible exception, indicating that endogenous production of or environmental contamination with acrylamide is low or nonexistent. The average ratio between the doses of glycidamide and acrylamide received (the concentration of free electrophilic agents integrated over time) in this group of workers was found to be 0.3. On the basis of the Hb adduct levels and the air concentrations in two of the workshops in this study (1.1 and 3.3 mg/cu m) and assuming 100% uptake of acrylamide through the air and an alveolar ventilation rate of 0.2 L/min per kg, it was concluded that there had been only minor exposure by inhalation and that dermal uptake was the dominant route of exposure.
/SIGNS AND SYMPTOMS/ May be harmful if inhaled. Causes respiratory tract irritation. May be harmful if absorbed through skin. Causes skin irritation. Causes eye irritation. Harmful if swallowed
The formation of glycidamide and acrylamide adducts on the N-terminal valine of hemoglobin (Hb) is directly proportional in man and rat. Comparison of free acrylamide in plasma, valine adducts on Hb and urinary S-(2-carboxyethyl)cysteine indicate that the rate of elimination of acrylamide is at least five times lower in man than in rats. Therefore, since the integrated concentration-time ratio for glycidamide to acrylamide adducts in man (0.3) is about one-half of that for rats (0.58) at low doses, the tissue dose of glycidamide may be higher in man than in rats, on the basis of an equal uptake of acrylamide.
Physiologically-based toxicokinetic ("pharmacokinetic") (PBPK or PBTK) modeling can be used as a tool to compare internal doses of acrylamide (AA) and its metabolite glycidamide (GA) in humans and rats. ... Excellent fits to a majority of the data for male Fischer 344 rats were obtained. Kinetic parameters for the human model were estimated based on fit to available human data for urinary metabolites of AA, and levels of hemoglobin adducts of AA and GA measured in studies in which human volunteers ingested known doses of AA. The simulations conducted with the rat and human models predicted that rats and humans ingesting comparable levels of AA (in mg/kg/day) would have similar levels of GA in blood and tissues. This finding stands in contrast to the default approach that assumes a 3.2-fold increase in human risk due to pharmacokinetic differences between rats and humans...
... This study used dual recirculating human placental perfusion to determine the transfer rate through the placenta of ... acrylamide and its genotoxic metabolite glycidamide. ... Placentas were collected immediately after delivery and kept physiologically functional as confirmed by antipyrine kinetics, glucose consumption and leak from fetal to maternal circulation. Acrylamide (5 or 10 ug/mL) or glycidamide (5 ug/mL), both with antipyrine (100 ug/mL), was added to maternal circulation. ... Acrylamide and glycidamide crossed the placenta from maternal to fetal circulation with similar kinetics to antipyrine, suggesting fetal exposure if the mother is exposed. The concentrations in maternal and fetal circulations equilibrated within 2 hr for both studied compounds and with both concentrations. Acrylamide metabolism into glycidamide was not detected during the 4-hr perfusions. Moreover, DNA adducts were undetectable in the placentas after perfusions...
The objective of this study was to compare the metabolism of acrylamide (AM) administered orally (po), dermally, intraperitoneally (ip), or by inhalation, and to measure the hemoglobin adducts produced. Rats and mice were exposed to 2.9 ppm (1,2,3-13C) and (2,3-14C)AM for 6 hr. (2,3-14C)AM (162 mg/kg) or (1,2,3-13C)AM (13 8 mg/kg) in water was administered dermally to rats for 24 hr, and (1,2,3-13C)AM was administered ip (47 mg/kg). Urine and feces were collected for 24 hr. Urine was the major elimination route in rats (ip, 62% and po, 53% of the dose; dermal, 44% of the absorbed dose; inhalation, 31% of the recovered radioactivity) and mice (inhalation, 27% of the recovered radioactivity). ... AM-GSH was a major metabolic route in rats accounting for 69% (ip), 71% (po), 52% (dermal), and 64% (inhalation). In mice, AM-GSH accounted for only 27% (inhalation) of the total urinary metabolites. The remaining urinary metabolites were derived from GA. Valine hemoglobin adducts of AM and GA were characterized using liquid chromatography-mass spectrometry. The ratio of AM to GA adducts paralleled the flux through pathways based on urinary metabolites. This study demonstrates marked species differences in the metabolism and internal dose (Hb-adducts) of AM following inhalation exposure and marked differences in uptake comparing dermal with po and ip administration.
... 110 5-6-year-old children were randomly selected. Their dietary habits as well as their exposure to the environmental tobacco smoke were assessed by means of a questionnaire. By means of spot urine samples, mercapturic acids of acrylamide (AAMA) and mercapturic acids of glycidamide (GAMA) were analyzed with LC-ESI-MS/MS. Median (95th percentile) urinary levels were 36.0 (152.7) ug AAMA/L and 13.4 (55.9) ug GAMA/L. Based on the metabolite levels, the median uptake of acrylamide was calculated to be 0.54 ug/kg BW/d. A number of associations with the consumption of French fries, various potato products, as well as fried cereals could be found...
Bicyclic pyrrolyl amides as glucogen phosphorylase inhibitors
申请人：——
公开号：US20030232875A1
公开（公告）日：2003-12-18
Heterocyclic amide derivatives, of formula (I): wherein —X-Y-Z- is selected from —S—CR
4
═CR
5
—, —CR
4
═CR
5
—S—, —O—CR
4
═CR
5
—, —CR
4
═CR
5
—O—, —N═CR
4
—S—, —S—CR
4
═N—, —NR
6
—CR
4
═CR
5
— and —CR
4
═CR
5
—NR
6
—; or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof; (with provisos); possess glycogen phosphorylase inhibitory activity and accordingly have value in the treatment of disease states associated with increased glycogen phosphorylase activity. Processes for the manufacture of said heterocyclic amide derivatives and pharmaceutical compositions containing them are described.
[EN] ANDROGEN RECEPTOR MODULATORS AND METHODS FOR THEIR USE<br/>[FR] MODULATEURS DU RÉCEPTEUR DES ANDROGÈNES ET LEURS PROCÉDÉS D'UTILISATION
申请人：ESSA PHARMA INC
公开号：WO2019226991A1
公开（公告）日：2019-11-28
Compounds having a structure of formula (I), (I-A), (Ia)-(Ie), (A)-(E), and (II) or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof are provided. Uses of such compounds for modulating androgen receptor activity, imaging diagnostics in cancer and therapeutics, and methods for treatment of disorders including prostate cancer are also provided.
Compounds of structure (I): having antibacterial activity are disclosed, including stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, wherein Q1, Q2, Q3, R8 and R9 are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
Syntheses of D-Labelled Oxidative Metabolites of Acrylamide and Acrylonitrile for the Quantification of Their Toxicities in Humans
作者：Vladimir N. Belov、Sergei M. Korneev、Jürgen Angerer、Armin de Meijere
DOI：10.1002/ejoc.200800291
日期：2008.9
Syntheses of the labelled oxidativemetabolites of acrylamide and acrylonitrile – reference compounds for the evaluation of human exposure to important toxicants – are reported. For that, L-cystine tert-butyl ester was acetylated and the product reductively cleaved to L-cysteine tert-butyl ester, which reacted with carbamoyl[D3]oxirane (obtained from [D3]acrylonitrile and 30 % aq. H2O2 at pH = 7.0–7
Synthesis of Glycidamide from Acrylonitrile Using Basic Hydrotalcite Catalyst in the Presence of Aqueous Hydrogen Peroxide and Unsaturated Amide
作者：Shinpei Fujiwara、Shun Nishimura、Kohki Ebitani
DOI：10.1246/cl.140658
日期：2014.11.5
Glycidamide (GA) can be synthesized from acrylonitrile (AN) by using hydrotalcite as a solid base catalyst and 25% aqueous H2O2 as an oxidant, in the presence of acrylamide (AA) as a cocatalyst in ...
