Prothioconazole was extensively metabolized in the rat following oral administration. Eighteen metabolites and the parent compound were identified in urine, feces and bile. The biotransformation of prothioconazole consisted of three major reaction types including desulfuration, oxidative hydroxylation of the phenyl moiety and glucuronic acid conjugation. Identification of the metabolites ranged from 26-63% of the administered dose. A higher percentage of metabolite isolation and identification could not be achieved due to difficulties in fecal extraction where 67-79% of the administered dose remained in non-extractable residues in the solids.
The major route of excretion for prothioconazole was in the feces, representing 22-53% of the administered dose. The parent compound prothioconazole was the most abundant in the feces (1-22% of the administered dose), followed by the prothioconazole-desthio metabolite (3-16% of the administered dose). All other fecal metabolites represented less than 7% of the administered dose. The 1,2,4-triazole metabolite was not detected in the feces. The major urinary metabolite was prothioconazole-S- or O-glucuronide (0.1-8% of the administered dose) and was preferentially excreted in females. The 1,2,4-triazole metabolite represented 0.8-2.3% of the administered dose following administration of single oral low and/or high doses. The remaining urinary metabolites accounted for 0-1.4% of the administered dose. Prothioconazole- S- or O-glucuronide was the most abundant metabolite in the bile, representing approximately 46% of the administered dose. This metabolite was excreted in females only in the urine, however, it was noted in the bile in males. The glucuronic acid metabolites in the bile represented 8-10% of the administered dose. Parent compound represented 3-5% of the administered dose in the bile. The 1,2,4-triazole metabolite was not detected in the bile.
来源:Hazardous Substances Data Bank (HSDB)
代谢
在一项代谢研究中，调查了prothioconazole-desthio的吸收、分布、代谢和排泄。放射性测试材料从胃肠道（GIT）的吸收在给药后仅4分钟就开始了。在1.5小时时观察到最高浓度为0.052微克/克。最大的放射性活性观察到在肝脏和GIT中，这可能是由于长时间的肠肝循环。其余组织的放射性活性水平低于1%。大于90%的给药放射性剂量通过胆汁和尿液排出。在呼出的二氧化碳中回收的给药放射性非常少。大部分给药的放射性剂量通过粪便排出，一小部分通过尿液排出。皮肤中含有微量的回收放射性活性，而胴体和GIT分别含有高达4%和2.25%。在48小时时，排泄可能没有完成，因为当时总体的放射性残留物是给药剂量的5到6%。消除半衰期被发现是44.3小时，平均滞留时间是48.2小时。这些观察结果表明，放射性在消除前重新分布到血浆的过程是缓慢的，这与总清除率为10.9 mL/min kg bw和肾清除率为1.4 mL/min kg bw相一致。在胆汁插管的动物中进行放射性剂量的十二指肠内给药后，24小时和48小时分别在胆汁中发现了84至85%的给药剂量。在这些动物中，48小时后通过尿液排出的剂量几乎占给药剂量的6%，而同一时间段内通过粪便排出的剂量占给药剂量的2%。在合并的胆汁样本中，观察到18个放射性HPLC峰，占总给药剂量的84.3%。五种化合物被分离和鉴定，而其余13种代谢物未被鉴定，占总给药剂量的44.7%。 /Prothioconazole-desthio/
In a metabolism study, the absorption, distribution, metabolism and excretion of prothioconazole-desthio were investigated. Absorption of the radioactive test material from the gastro-intestinal tract (GIT) commenced as early as 4 minutes following dosing. A maximum concentration of 0.052 ug/g was observed at 1.5 hours. The largest amount of radioactivity was observed in the liver and the GIT, likely due to long-lasting enterohepatic circulation. The remaining tissues contained levels of radioactivity of less than 1%. Greater than 90% of the administered radioactive dose was excreted in the bile and urine. Very little of the administered radioactivity was recovered in the expired carbon dioxide. The majority of the radioactive administered dose was excreted in the feces, with a minor portion being excreted in the urine. The skin contained a minute amount of the recovered radioactivity, while the carcass and GIT contained up to 4 and 2.25%, respectively. Excretion was not likely complete at 48 hours, as the total body radioactive residue was 5 to 6% of the administered dose at that time point. The elimination half-life was found to be 44.3 hours, and the mean residence time was 48.2 hours. These observations indicate that the process of redistribution of the radioactivity into the plasma before elimination was slow, as supported by the total clearance of 10.9 mL/min kg bw and the renal clearance of 1.4 mL/min kg bw. Following the intraduodenal administration of the radioactive dose in bile-cannulated animals, 84 to 85% of the administered dose was found in the bile after 24 and 48 hours, respectively. Excretion in urine in these animals accounted for almost 6% of the administered dose after 48 hours, while excretion in faeces accounted for 2% of the administered dose for the same time period. In the pooled bile sample, 18 radioactive HPLC peaks were observed accounting for 84.3% of the administered dose. Five compounds were isolated and identified, while the remaining 13 metabolites were not identified, accounting for 44.7% of the administered dose. /Prothioconazole-desthio/
In whole-body autoradiography experiments, the quick onset of absorption of the test material was demonstrated. Absorption was not complete after one hour. The autoradiograms also showed that the blood concentration was less than the concentration present in the fatty tissues, demonstrating the lipophilic nature of prothioconazole-desthio, and perhaps of its metabolites. The mucous membrane of the stomach walls were observed with radioactivity throughout the various observation periods, which was considered an indication of extrabiliary secretion of the absorbed radioactivity back into the stomach lumen. The muscle, heart, lung, brain, thyroid, and mineral portion of the bones showed minor concentrations of radioactivity. The testes had a radioactivity distribution pattern indicative of the blood circulation in the organ. Medium amounts of radioactivity were observed in some glandular organs, including the preputial gland and the adrenals. The gums were also observed with increased radioactivity, with unknown physiological significance. The distributions noted at one hour were fairly consistent for 48 hours, though declining due to excretion. The renal cortex contained radioactivity to a much greater extent than did the renal pelvis, indicating that the radioactivity was reabsorbed in the duodenum. As well, the radioactivity that is absorbed is likely not transformed into metabolites that are adequately polar to be eliminated by the kidney. This results in increased passage through the liver by the radioactive test material. /Prothioconazole-desthio/
The available studies in the mouse and rat show no increase in tumor incidence. Therefore, the Health Effects Division /of the USEPA/ has concluded prothioconazole or its metabolites are not carcinogenic, and are classified "Not likely to be Carcinogenic to Humans" according to the 2005 Cancer Guidelines.
/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/
/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/
/LABORATORY ANIMALS: Acute Exposure/ Prothioconazole has low acute toxicity by oral, dermal, and inhalation routes. It is not a dermal sensitizer, or a skin or eye irritant. Prothioconazole-desthio also has low acute toxicity by oral, dermal, and inhalation routes. It is not a dermal sensitizer, or a skin irritant, but it is a slight eye irritant.
Following single oral low dose administration, the absorption of prothioconazole in male rats was approximately 94% for the triazole label. The absorption for the phenyl label was estimated to be approximately 90% at 48 hours based on extrapolation of the course of excretion for the triazole label at 48 hours. Plasma radioactivity time-course data showed that absorption following single oral low dose administration was rapid, with peak plasma concentrations occurring between 0.33 and 0.66 hours post administration in males and females. Peak plasma concentrations following single oral high dose administration occurred between 0.66 and 1.00 hours post administration in males and females. The absorption of the phenyl-labelled prothioconazole was slightly more rapid, with peak plasma concentrations occurring between 0.16 and 0.33 hours post administration of a single oral low dose in males, and at 0.16 hours post administration of a repeat oral low dose in males and females. Oscillations in the plasma time course were noted, indicating that the radioactivity was subjected to enterohepatic circulation. This effect was more prominent in the female rats. A slight delay in absorption compared to males was also noted in females.
Residual radioactivity in the rats 168 hours after a single oral low dose administration was low. For the triazole label, 1.5% of the administered dose was recovered in the tissues and carcass of males, and 0.4% was recovered in females. The highest tissue levels were found in liver, carcass and gastrointestinal tract. In all other tissues examined, residual radioactivity levels ranged from 0.0004-0.07%. For the phenyl label (administered to males only), 5.8% of the administered dose was recovered in the tissues and carcass. The highest tissue levels were found in the gastrointestinal tract, liver and carcass. In all other tissues examined, residual radioactivity levels ranged from 0.0001-0.05%. Residual radioactivity in the rats 48 hours after a repeat oral low dose administration was also low, with 3.8% of the administered dose recovered in the tissues and carcass of males, and 0.8% recovered in females. The highest tissue levels were found in liver, gastrointestinal tract and carcass. In all other tissues examined, residual radioactivity levels ranged from 0.0002-0.05%. Total body accumulation as well as liver accumulation was consistently higher in males. Residual radioactivity in the rats 168 hours after a single oral high dose administration was also low, with 0.11% of the administered dose recovered in the carcass and tissues of both males and females. Total body accumulation was approximately the same in males and females, with liver accumulation higher in the males.
The primary route of excretion for both labels and both sexes was via the feces. Following single oral low dose administration (triazole label), total recovery was approximately 94-95% of the administered dose for both sexes, with 10% (males) and 16% (females) of the administered dose eliminated in the urine, and 84% (males) and 78% (females) eliminated in the feces. In the phenyl-labelled group (males only), 5% of the administered dose was eliminated in the urine and 85% in the feces, for a total recovery of approximately 90%. In the bile duct-cannulated triazolelabel group (males only), approximately 90% of the administered dose was eliminated in the bile within 24-48 hours. In the phenyl-label group (males only), approximately 81% of the administered dose was eliminated in the bile after 24 hours and 93% after 48 hours.
In a whole body autoradiography distribution study, peak concentrations in males were noted 1 hour post-administration and continued to decline until sacrifice at 168 hours. In females, absorption was slightly delayed with peak concentrations in some tissues noted at 8 hours post-administration. The highest concentrations were noted in liver (up to 1.78 g/g in males and up to 0.97 ug/g in females), followed by kidney (renal medulla, up to 0.64 g/g), brown/perirenal fat (up to 0.36 ug/g), thyroid (up to 0.23 ug/g) and adrenal gland (up to 0.27 ug/g). All other tissues showed peak concentrations of <0.13 ug/g. Concentrations of radioactivity decreased rapidly from 24 to 168 hours post-administration, indicative of continued elimination from the tissues.
[EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
申请人：GILEAD APOLLO LLC
公开号：WO2017075056A1
公开（公告）日：2017-05-04
The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.
[EN] BICYCLYL-SUBSTITUTED ISOTHIAZOLINE COMPOUNDS<br/>[FR] COMPOSÉS ISOTHIAZOLINE SUBSTITUÉS PAR UN BICYCLYLE
申请人：BASF SE
公开号：WO2014206910A1
公开（公告）日：2014-12-31
The present invention relates to bicyclyl-substituted isothiazoline compounds of formula (I) wherein the variables are as defined in the claims and description. The compounds are useful for combating or controlling invertebrate pests, in particular arthropod pests and nematodes. The invention also relates to a method for controlling invertebrate pests by using these compounds and to plant propagation material and to an agricultural and a veterinary composition comprising said compounds.
The present invention relates to azoline compounds of formula (I) wherein A, B1, B2, B3, G1, G2, X1, R1, R3a, R3b, Rg1 and Rg2 are as defined in the claims and the description. The compounds are useful for combating or controlling invertebrate pests, in particular arthropod pests and nematodes. The invention also relates to a method for controlling invertebrate pests by using these compounds and to plant propagation material and to an agricultural and a veterinary composition comprising said compounds.
[EN] SUBSTITUTED QUINAZOLINES AS FUNGICIDES<br/>[FR] QUINAZOLINES SUBSTITUÉES, UTILISÉES EN TANT QUE FONGICIDES
申请人：SYNGENTA PARTICIPATIONS AG
公开号：WO2010136475A1
公开（公告）日：2010-12-02
The present invention relates to a compound of formula (I) wherein wherein the substituents have the definitions as defined in claim 1or a salt or a N-oxide thereof, their use and methods for the control and/or prevention of microbial infection, particularly fungal infection, in plants and to processes for the preparation of these compounds.
