1-[4-[4-[[(4S)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 1-[4-[4-[[(4S)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone
• 化学式: C₂₆H₂₈Cl₂N₄O₄
• 分子量: 531.4
• InChiKey: XMAYWYJOQHXEEK-ZZHFZYNASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  36
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  69.1
• 氢给体数：
  0
• 氢受体数：
  6

ADMET

代谢

酮康唑部分在肝脏中通过氧化和降解咪唑环和哌嗪环、氧化O-脱烷基化以及芳香族羟基化代谢为几种无活性代谢物。

Ketoconazole is partially metabolized, in the liver, to several inactive metabolites by oxidation and degradation of the imidazole and piperazine rings, by oxidative O-dealkylation, and by aromatic hydroxylation.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

鉴定和使用：酮康唑被用作抗真菌药物。人类接触和毒性：在酮康唑治疗期间，血清天门冬氨酸转氨酶（AST）、丙氨酸转氨酶（ALT）和碱性磷酸酶浓度可能会暂时增加。接受口服酮康唑治疗的患者中发生了严重肝毒性，包括一些致命的病例或需要肝移植的病例。肝毒性可能是肝细胞型（大多数情况下）、胆汁淤积型或混合型损伤。尽管酮康唑引起的肝毒性通常在停药后可逆，但恢复可能需要几个月，罕见情况下会导致死亡。症状性肝毒性通常在酮康唑治疗的前几个月内明显，但偶尔也可能在治疗的第一周内出现。一些因酮康唑引起肝毒性的患者没有明显的肝脏疾病风险因素。在接受高剂量口服酮康唑短期治疗的患者和接受低剂量口服药物长期治疗的患者中报告了严重肝毒性。许多报告的肝毒性病例发生在接受药物治疗甲癣（甲真菌病）或慢性、难治性皮肤真菌病的患者中。酮康唑引起的肝炎在一些儿童中也有报告。通常剂量（即每日200-400毫克）的酮康唑已被报告暂时（持续2-12小时）抑制睾丸睾酮合成。血清促黄体生成激素（LH）浓度可能会出现代偿性增加。每日800-1200毫克的剂量已被报告对睾酮合成有更持久的影响；在一项研究中，接受这些高剂量的男性中，大约30%的接受800毫克每日治疗的人和所有接受1200毫克每日治疗的人，其血清睾酮浓度一整天都保持在亚正常水平（即小于300 ng/dL）。精子减少、性欲减退和阳痿在这些男性中经常发生，而无精子症则很少发生。该药物显然在体内外直接抑制肾上腺类固醇和睾酮的合成。酮康唑主要通过阻断几种P-450酶系统（例如，11β-羟基化酶、C-17,20-裂解酶、胆固醇侧链裂解酶）来抑制类固醇合成。总的来说，结果表明许多常用的唑类杀菌剂在体内作为内分泌干扰物发挥作用，尽管在体内的作用模式有所不同。由于酮康唑已知在人类中引起许多内分泌干扰效应。动物研究：口服给药后，在小鼠、大鼠和豚鼠中通过镇静、僵直、共济失调、震颤、惊厥和致死前失去翻正反射（剂量大于320 mg/kg）表现出毒性。在狗中，毒性表现为腹泻和呕吐（剂量大于80 mg/kg）。酮康唑已通过口服（灌胃）和静脉途径给予小鼠、大鼠、豚鼠和狗。静脉给药后的毒性在小鼠、大鼠和豚鼠中表现为痉挛、惊厥和呼吸困难；小鼠和豚鼠在致死前失去翻正反射，狗也表现出毒性。狗的毒性还表现为舔舐和惊厥。在大鼠中，治疗组和对照组之间的肿瘤发生率和类型没有显著差异，除了高剂量雌性大鼠的总体肿瘤率降低。在大鼠发育研究中，死胎发生率从对照组的0.5%增加到40 mg/kg剂量组的32.7%，并且在两个窝中发生了食仔现象。在小鼠中，尾部附睾的精子活动力和密度显著下降。接受酮康唑治疗的小鼠的生育力显著下降（50%阴性）。睾丸、附睾、精囊和腹侧前列腺的总蛋白质和唾液酸含量显著减少。睾丸的胆固醇含量升高，而精囊的果糖含量显著降低。酮康唑治疗改变了生殖道的生化环境。在兔中，酮康唑在高剂量40 mg/kg/天时表现出母体毒性、胚胎毒性和致畸性。在使用显性致死突变试验或Ames沙门氏菌微囊体激活试验评估时，酮康唑没有显示出任何突变潜力。生态毒性研究：酮康唑诱导了鳟鱼中的CYP1A和CYP3A表达。然而，酮康唑最显著的效果是在鳟鱼和孔雀鱼中CYP3A催化活性减少了60至90%。

IDENTIFICATION AND USE: Ketokonazole is used as antifungal medication. HUMAN EXPOSURE AND TOXICITY: Transient increases in serum AST, ALT, and alkaline phosphatase concentrations may occur during ketoconazole therapy. Serious hepatotoxicity has occurred in patients receiving oral ketoconazole, including cases that were fatal or required liver transplantation. Hepatotoxicity may be hepatocellular (in most cases), cholestatic, or a mixed pattern of injury. Although ketoconazole-induced hepatotoxicity usually is reversible following discontinuance of the drug, recovery may take several months and rarely death has occurred. Symptomatic hepatotoxicity usually is apparent within the first few months of ketoconazole therapy, but occasionally may be apparent within the first week of therapy. Some patients with ketoconazole-induced hepatotoxicity had no obvious risk factors for liver disease. Serious hepatotoxicity has been reported in patients receiving high oral ketoconazole dosage for short treatment durations and in patients receiving low oral dosage of the drug for long durations. Many of the reported cases of hepatotoxicity occurred in patients who received the drug for the treatment of tinea unguium (onychomycosi or the treatment of chronic, refractory dermatophytoses. Ketoconazole-induced hepatitis has been reported in some children. Usual dosages (ie, 200-400 mg daily) of ketoconazole have been reported to transiently (for 2-12 hours) inhibit testicular testosterone synthesis. A compensatory increase in serum luteinizing hormone (LH) concentrations may occur. Dosages of 800-1200 mg daily have been reported to have a more prolonged effect on testosterone synthesis; in one study in males receiving these high dosages, serum testosterone concentrations remained at a subnormal level (ie, less than 300 ng/dL) throughout the day in about 30% of those receiving 800 mg daily and in all of those receiving 1200 mg daily. Oligospermia, decreased libido, and impotence often occurred in these males and azoospermia occurred rarely. The drug apparently directly inhibits synthesis of adrenal steroids and testosterone in vitro and in vivo. Ketoconazole appears to inhibit steroid synthesis principally by blocking several P-450 enzyme systems (eg, 11beta-hydroxylase, C-17,20-lyase, cholesterol side-chain cleavage enzyme). Overall the results show that many of the commonly used azole fungicides act as endocrine disruptors in vivo, although the profile of action in vivo varies. As ketoconazole is known to implicate numerous endocrine-disrupting effects in humans. ANIMAL STUDIES: After oral administration toxicity was manifested in mice, rats and guinea pigs by sedation, catalepsy, ataxia, tremors, convulsions and pre-lethal loss of the righting reflex at doses >320 mg/kg. In dogs, toxicity was manifested by diarrhea and vomiting at doses >80 mg/kg. Ketoconazole has been administered by the oral (gavage) and intravenous routes to mice, rats, guinea pigs and dogs. Toxicity after intravenous administration was manifested by spasms, convulsions and dyspnea in rats, mice and guinea pigs; pre-lethal loss of the righting reflex occurred in mice and guinea pigs, and dogs. Toxicity in dogs was also manifested by licking and convulsions. In rats the overall incidence of and type of tumors was not significantly different between treated and control groups, except for high-dosed female rats who had a decrease of the overall tumor rate. In developmental studies in rats the incidence of stillborn fetuses increased from a control value of 0.5% to 32.7% in rats dosed with 40 mg/kg and cannibalization of young occurred in two litters. In mice a significant decline in sperm motility and density in cauda epididymis was noted. A sharp decline in fertility (50% negative) in ketoconazole treated mice was observed. A significant reduction in the total protein and sialic acid contents of testes, epididymis, seminal vesicle and ventral prostate were noticed. The cholesterol contents of testes were raised while fructose contents of seminal vesicle were reduced significantly. The ketoconazole treatment altered the biochemical milieu of the reproductive tract. In the rabbit, ketoconazole produces evidence of maternal toxicity, embryotoxicity and teratogenicity at a high dose of 40 mg/kg/day. Ketoconazole did not show any signs of mutagenic potential when evaluated using the dominant lethal mutation test or the Ames Salmonella microsomal activator assay. ECOTOXICITY STUDIES: Ketoconazole induced CYP1A and CYP3A expression in rainbow trout. However, the most pronounced effect of ketoconazole was a 60 to 90% decrease in CYP3A catalytic activities in rainbow trout and in killifish.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 肝毒性

口服酮康唑的患者中，有4%至20%的人会出现轻度和短暂的肝酶升高。这些异常通常是暂时的和无症状的，很少需要调整剂量或停药。文献中详细描述了酮康唑引起的临床明显肝毒性，估计发生的概率为每2000至15000名使用者中有一名。肝损伤通常在开始治疗后的1至6个月内呈现急性肝炎样的表现。虽然大多数病例呈现肝细胞损伤的模式，但也描述了胆汁淤积的形式。皮疹、发热和嗜酸性粒细胞增多是罕见的，自身抗体的形成也是如此。停止治疗后的恢复可能延迟，通常需要1到3个月。已经描述了出现急性肝衰竭、死亡或需要紧急肝移植的严重病例。

Mild and transient elevations in liver enzymes occur in 4% to 20% of patients on oral ketaconazole. These abnormalities are usually transient and asymptomatic and uncommonly require dose adjustment or discontinuation. Clinically apparent hepatotoxicity from ketaconazole is well described in the literature and is estimated to occur in 1:2,000 to 1:15,000 users. The liver injury typically presents with an acute hepatitis-like picture 1 to 6 months after starting therapy. While most cases present with a hepatocellular pattern of injury, cholestatic forms have been described. Rash, fever and eosinophilia are rare as is autoantibody formation. Recovery upon stopping therapy may be delayed and generally takes 1 to 3 months. Severe cases with acute liver failure and death or need for emergency liver transplantation have been described.

来源:LiverTox

毒理性

• 暴露途径

该物质可以通过摄入被身体吸收。

The substance can be absorbed into the body by ingestion.

来源:ILO International Chemical Safety Cards (ICSC)

毒理性

• 吸入症状

咳嗽。

Cough.

来源:ILO International Chemical Safety Cards (ICSC)

毒理性

• 皮肤症状

Redness.

Redness.

来源:ILO International Chemical Safety Cards (ICSC)

吸收、分配和排泄

酮康唑从胃肠道迅速吸收。口服给药后，酮康唑在胃液中溶解并转化为盐酸形式，然后从胃部吸收。

Ketoconazole is rapidly absorbed from the GI tract. Following oral administration, ketoconazole is dissolved in gastric secretions and converted to the hydrochloride salt prior to absorption from the stomach.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

食物对酮康唑在胃肠道吸收的速度和程度的影响尚未明确确定。一些临床医生报告称，与食物同服相比，空腹服用酮康唑会导致更高的血药浓度。然而，制造商表示，与食物同服酮康唑可以增加吸收的程度，并使血药浓度更加一致。制造商建议，食物通过增加酮康唑的溶解速度和/或程度（例如，通过增加胆汁分泌）或延迟胃排空来增加酮康唑的吸收。

The effect of food on the rate and extent of GI absorption of ketoconazole has not been clearly determined. Some clinicians have reported that administration of ketoconazole to fasting individuals results in higher plasma concentrations of the drug than does administration with food. However, the manufacturer states that administration of ketoconazole with food increases the extent of absorption and results in more consistent plasma concentrations of the drug. The manufacturer suggests that food increases absorption of ketoconazole by increasing the rate and/or extent of dissolution of ketoconazole (e.g., by increasing bile secretions) or by delaying stomach emptying.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

酮康唑是一种弱的双性剂，因此需要酸性环境才能溶解和被吸收。

Ketoconazole is a weak dibasic agent and thus requires acidity for dissolution and absorption.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

口服酮康唑的生物利用度取决于胃内胃内容的pH值；pH值增加会导致药物吸收减少。在获得性免疫缺陷综合症（AIDS）患者中报告了酮康唑的生物利用度降低，这可能是由于该病状相关的胃低氯血症；在这些患者中，同时给予稀释的盐酸溶液可以正常化药物的吸收。198 同时给予酸性饮料可能会增加某些无胃酸个体的口服酮康唑的生物利用度。

The bioavailability of oral ketoconazole depends on the pH of the gastric contents in the stomach; an increase in the pH results in decreased absorption of the drug. Decreased bioavailability of ketoconazole has been reported in patients with acquired immunodeficiency syndrome (AIDS), probably because of gastric hypochlorhydria associated with this condition; concomitant administration of dilute hydrochloric acid solution normalized absorption of the drug in these patients.198 Concomitant administration of an acidic beverage may increase bioavailability of oral ketoconazole in some individuals with achlorhydria.

来源:Hazardous Substances Data Bank (HSDB)

文献信息

• TREATMENT OF ACANTHAMOEBA OR BALAMUTHIA TROPHOZOITES AND/OR CYSTS
  申请人：GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION, INC.

  公开号：US20220096441A1

  公开（公告）日：2022-03-31

  Compounds, compositions, and methods for the treatment of infections caused by Acanthamoeba or Balamuthia mandrillaris trophozoites and/or cysts and for the disinfection of solids and/or liquids, such as medical and personal care items, for example contact lenses, that may harbor Acanthamoeba trophozoites and/or cysts are provided.