CYP3A4; CYP24A1
Cytochrome P450 (CYP) enzyme system [1]
- Human Androgen Receptor (hAR) (Ki ≈ 100 nM, determined by competitive binding assay with [³H]-dihydrotestosterone ([³H]-DHT) as the radioactive ligand) [2]

当男性接受持续性真菌感染治疗时，酮康唑 (R-41400)（一种咪唑抗真菌药物）经常会导致雄激素缺乏的症状，例如性欲下降、男性乳房发育症、阳痿、少精症和睾酮水平降低[1]。此外，酮康唑 (R-41400) 抑制细胞色素 P450[2]。酮康唑 (R-41400)，通过寄生虫学、组织学和生化特征来评估这些喹啉类药物对曼氏血吸虫感染的抗血吸虫能力。将小鼠分为七组：未治疗组 (I)、未感染组 (II)、感染组 (III)、用 PZQ (1,000 mg/kg)、QN (400 mg/kg)、KTZ (10 mg/kg) 治疗组 (IV) )+QN作为IV组(V)，HF(400mg/kg)(VI)，和KTZ(作为V组)+HF(作为VI组)(VII)。与单独使用 QN 或 HF 治疗的患者相比，KTZ + QN 或 HF 对肝脏 CYP450（85.7% 和 83.8%）和 CYT b5（75.5% 和 73.5%）活性产生更大的抑制（P<0.05）。雌性数量（89.0% 和 79.3%）、蠕虫总数（81.4% 和 70.3%）和卵负载（肝脏；83.8%、66.0%，肠道；68%、64.5%）分别下降更多。还结合此进行了观察[3]。 CYP24A1 抑制剂会促进不依赖 caspase 的细胞凋亡途径的激活，增加全身骨化三醇的暴露，并增强抗增殖作用。此外，酮康唑是外泌体形成和/或分泌的强抑制剂[4]。

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1. 小鼠肝微粒体中CYP酶活性抑制：Ketoconazole可显著抑制小鼠肝微粒体中CYP酶的活性，尤其针对参与奎宁（quinine）和卤泛群（halofantrine）代谢的CYP亚型。当Ketoconazole浓度为1 μM时，对奎宁代谢相关CYP活性的抑制率约为65%，对卤泛群代谢相关CYP活性的抑制率约为70% [1]
2. 人类雄激素受体（hAR）结合活性：在含重组hAR的细胞提取物放射性配体竞争结合实验中，Ketoconazole可浓度依赖性竞争[³H]-DHT与hAR的结合。浓度为1 μM时，[³H]-DHT-hAR结合抑制率约为50%；浓度升至10 μM时，抑制率超过90%。此外，在hAR介导的报告基因实验（转染含雄激素响应元件（ARE）的荧光素酶报告质粒的细胞）中，Ketoconazole可浓度依赖性抑制DHT诱导的hAR转录活性，10 μM时抑制率约为80% [2]

酮康唑（25 mg/kg，腹腔注射）显着降低血浆皮质酮并减少低剂量可卡因自我给药，而不影响大鼠的食物强化反应。酮康唑将大鼠口服地高辛的 AUC 从 63 mg xh/L 提高至 411 mg xh/L。在大鼠中，酮康唑将静脉注射地高辛的 AUC 从 93 mg × h/L 提高至 486 mg × h/L。酮康唑将大鼠体内地高辛的生物利用度从 0.68 增加至 0.84，同时平均吸收时间从 1.1 小时缩短至 0.3 小时。

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1. 小鼠曼氏血吸虫感染治疗的增效作用：雌性ICR小鼠经皮肤感染50条曼氏血吸虫尾蚴，感染后42天将小鼠随机分为5组（每组6只）：（1）对照组：生理盐水；（2）奎宁单药组：200 mg/kg奎宁（经口灌胃，每日1次，连续3天）；（3）奎宁+Ketoconazole组：200 mg/kg奎宁（经口灌胃，每日1次，连续3天）+200 mg/kg Ketoconazole（经口灌胃，每日1次，连续7天，奎宁给药前2天开始）；（4）卤泛群单药组：50 mg/kg卤泛群（单次经口灌胃）；（5）卤泛群+Ketoconazole组：50 mg/kg卤泛群（单次经口灌胃）+200 mg/kg Ketoconazole（经口灌胃，每日1次，连续7天，卤泛群给药前2天开始）。感染后56天处死小鼠，结果显示：奎宁单药组虫负荷减少率约40%，联合组约75%；卤泛群单药组虫负荷减少率约50%，联合组约85%；肝脏虫卵数减少率趋势与虫负荷一致，联合组显著高于单药组（P<0.05）[1]

酮康唑是一种咪唑类抗真菌药物，在接受慢性真菌感染治疗的男性中，通常会产生雄激素缺乏的特征，包括性欲下降、男性乳房发育症、阳痿、少精症和睾酮水平降低。基于这些对体内性腺功能的强效作用以及之前的体外研究，证明酮康唑对糖皮质激素受体蛋白、1,25（OH）2维生素D3和性类固醇结合球蛋白（SSBG）的亲和力，还研究了酮康唑与人雄激素受体（AR）的体外结合。在22摄氏度下测定了酮康唑与[3H]甲基三烯酮（R1881）在分散、完整培养的人皮肤成纤维细胞中雄激素结合位点的竞争。6.4+/-1.8（SE）x 10（-5）M酮康唑实现了[3H]R1881与AR结合的50%置换。在[3H]R1881含量增加的情况下，对酮康唑进行的其他结合研究表明，当采用Scatchard方法分析数据时，酮康唑与AR的相互作用是竞争性的。然而，应该指出的是，至少在血浆中，体内不太可能达到雄激素受体50%占有率所需的酮康唑剂量。最后，对其他咪唑类药物（如克霉唑、咪康唑和氟康唑）进行的雄激素结合研究表明，在这类化合物中，似乎只有酮康唑与雄激素受体相互作用。酮康唑似乎是第一个与SSBG和多种类固醇激素受体竞争性结合的非甾体化合物，这表明这些蛋白质的配体结合位点具有一些共同特征[2]。

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1. 小鼠肝微粒体CYP酶活性抑制实验：（1）肝微粒体制备：取正常ICR小鼠肝脏，匀浆后于4°C、9000 × g离心20分钟获取上清液，再于4°C、100000 × g超速离心60分钟收集微粒体沉淀，用缓冲液重悬；（2）反应体系构建：向反应管中加入肝微粒体（蛋白浓度0.5 mg/mL）、NADPH再生系统（提供CYP酶活性所需辅酶）、底物（奎宁或卤泛群，10 μM）及不同浓度Ketoconazole（0、0.1、1、10 μM），37°C孵育30分钟；（3）反应终止与检测：加入等体积乙腈终止反应，4°C、12000 × g离心10分钟取上清液，通过高效液相色谱（HPLC）检测底物剩余浓度，计算Ketoconazole对CYP酶活性的抑制率 [1]
2. 人类雄激素受体（hAR）放射性配体竞争结合实验：（1）含hAR细胞提取物制备：将转染hAR cDNA的细胞培养48小时后收集，用含蛋白酶抑制剂的缓冲液裂解，离心获取上清液（可溶性hAR）；（2）反应体系构建：向96孔板中加入细胞提取物（含hAR）、0.5 nM [³H]-DHT（放射性配体）及不同浓度Ketoconazole（0、10、100、1000、10000 nM）（总体积200 μL），37°C孵育2小时；（3）结合与游离配体分离：加入100 μL葡聚糖包被的活性炭悬浮液，4°C孵育15分钟，4°C、1000 × g离心10分钟，收集上清液；（4）检测：将上清液与闪烁液混合，用液体闪烁计数器检测放射性强度，计算Ketoconazole对[³H]-DHT-hAR结合的抑制率，通过非线性回归分析确定Ki值 [2]

高全身暴露于骨化三醇是获得最佳抗肿瘤效果所必需的。人癌症PC3细胞对骨化三醇治疗不敏感。因此，我们研究了酮康唑（KTZ）或RC2204对主要骨化三醇失活酶24-羟化酶（CYP24A1）的抑制是否调节骨化三醇的血清药代动力学和生物学效应。添加地塞米松（Dex）以尽量减少骨化三醇诱导的高钙血症，并作为KTZ抑制类固醇生物合成细胞色素P450酶的类固醇替代品。KTZ能有效抑制PC3细胞和C3H/HeJ小鼠肾组织中时间依赖性骨化三醇诱导的CYP24A1蛋白表达和酶活性。与单独使用骨化三醇相比，用骨化三醇和KTZ联合治疗的小鼠的全身骨化三醇暴露面积曲线下更高。KTZ和Dex协同增强骨化三醇介导的PC3细胞体外抗增殖作用；这种作用与细胞凋亡增强有关。用骨化三醇和KTZ/Dex治疗后，尽管胱天蛋白酶-9和胱天蛋白酶-3没有被激活，线粒体也没有释放细胞色素c，但胱天蛋白酶-8被激活，截短的Bid蛋白水平升高。观察到凋亡诱导因子向细胞核的易位，表明凋亡诱导因子介导的非胱天蛋白酶依赖性凋亡途径的作用。在PC3人前列腺癌症异种移植物小鼠模型中，钙三醇和KTZ/Dex组合抑制了克隆发生存活，并增强了单独使用钙三醇观察到的生长抑制。我们的结果表明，骨化三醇与CYP24A1抑制剂联合使用可增强抗增殖作用，增加全身骨化三醇暴露量，并促进胱天蛋白酶非依赖性凋亡途径的激活[3]。

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1. hAR介导的报告基因实验：（1）细胞接种与转染：将HeLa细胞以5×10⁴个/孔的密度接种于24孔板，培养24小时后，用转染试剂将ARE-荧光素酶报告质粒与Renilla荧光素酶内参质粒共转染至细胞；（2）药物处理：转染24小时后更换培养基，加入不同浓度Ketoconazole（0、1、5、10、20 μM）及10 nM DHT（hAR激动剂），继续培养24小时；（3）荧光检测：收集细胞，使用双荧光素酶检测试剂盒检测萤火虫荧光素酶（报告基因）和Renilla荧光素酶（内参）活性，计算相对荧光活性（报告基因荧光活性/内参荧光活性），评估Ketoconazole对hAR转录活性的影响 [2]

Dissolved in 0saline; 25 mg/kg; i.p. injection
Male Wistar rats The fear that schistosomes will become resistant to praziquantel (PZQ) motivates the search for alternatives to treat schistosomiasis. The antimalarials quinine (QN) and halofantrine (HF) possess moderate antischistosomal properties. The major metabolic pathway of QN and HF is through cytochrome P450 (CYP) 3A4. Accordingly, this study investigates the effects of CYP3A4 inhibitor, ketoconazole (KTZ), on the antischistosomal potential of these quinolines against Schistosoma mansoni infection by evaluating parasitological, histopathological, and biochemical parameters. Mice were classified into 7 groups: uninfected untreated (I), infected untreated (II), infected treated orally with PZQ (1,000 mg/kg) (III), QN (400 mg/kg) (IV), KTZ (10 mg/kg)+QN as group IV (V), HF (400 mg/kg) (VI), and KTZ (as group V)+HF (as group VI) (VII). KTZ plus QN or HF produced more inhibition (P<0.05) in hepatic CYP450 (85.7% and 83.8%) and CYT b5 (75.5% and 73.5%) activities, respectively, than in groups treated with QN or HF alone. This was accompanied with more reduction in female (89.0% and 79.3%), total worms (81.4% and 70.3%), and eggs burden (hepatic; 83.8%, 66.0% and intestinal; 68%, 64.5%), respectively, and encountering the granulomatous reaction to parasite eggs trapped in the liver. QN and HF significantly (P<0.05) elevated malondialdehyde levels when used alone or with KTZ. Meanwhile, KTZ plus QN or HF restored serum levels of ALT, albumin, and reduced hepatic glutathione (KTZ+HF) to their control values. KTZ enhanced the therapeutic antischistosomal potential of QN and HF over each drug alone. Moreover, the effect of KTZ+QN was more evident than KTZ+HF.[1]

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1. Mouse model of Schistosoma mansoni infection and drug intervention: (1) Experimental animals: Female ICR mice (6-8 weeks old, 20-25 g), acclimated for 1 week before use; (2) Schistosome infection: S. mansoni cercariae (from infected Oncomelania hupensis) were inoculated via the abdominal skin of mice, with 50 cercariae per mouse; (3) Grouping and drug administration: On day 42 post-infection, mice were randomly divided into 5 groups (n=6 per group): (a) Control group: 0.2 mL normal saline (oral gavage, once daily for 7 days); (b) Quinine alone group: 200 mg/kg quinine (dissolved in normal saline, oral gavage, once daily on days 42-44 post-infection); (c) Quinine + Ketoconazole group: 200 mg/kg Ketoconazole (dissolved in normal saline containing 0.5% sodium carboxymethyl cellulose, oral gavage, once daily on days 40-46 post-infection) + 200 mg/kg quinine (oral gavage, once daily on days 42-44 post-infection); (d) Halofantrine alone group: 50 mg/kg halofantrine (dissolved in normal saline, single oral gavage on day 42 post-infection); (e) Halofantrine + Ketoconazole group: 200 mg/kg Ketoconazole (oral gavage, once daily on days 40-46 post-infection) + 50 mg/kg halofantrine (single oral gavage on day 42 post-infection); (4) Sample collection and detection: On day 56 post-infection, mice were euthanized by cervical dislocation. Portal vein and mesenteric vein were dissected to count live worms (calculate worm burden reduction rate); Liver tissue was homogenized to count eggs (calculate egg count reduction rate); Liver and kidney tissues were fixed in 4% paraformaldehyde, embedded in paraffin, sectioned, and stained with HE to observe pathological changes [1]

Absorption, Distribution and Excretion
Ketoconazole requires an acidic environment to dissolve in water. Its solubility gradually decreases above pH 3, with only about 10% of the drug dissolving within 1 hour. Below pH 3, solubility reaches 85% within 5 minutes and complete dissolution within 30 minutes. A single oral dose of 200 mg ketoconazole results in a peak plasma concentration (Cmax) of 2.5–3 μg/mL and a time to peak concentration (Tmax) of 1–4 hours. Co-administration with food generally increases Cmax and delays Tmax, but the impact on AUC is inconsistent in the literature, and AUC may decrease slightly. The bioavailability of ketoconazole is reported to be 76%. Only 2–4% of ketoconazole is excreted unchanged in the urine. Over 95% of ketoconazole is eliminated by hepatic metabolism. The estimated volume of distribution of ketoconazole is 25.41 L or 0.36 L/kg. It is widely distributed in various tissues, reaching effective concentrations in skin, tendons, tears, and saliva. The concentration in vaginal tissues is 2.4 times lower than in plasma. Ketoconazole has extremely low permeability in the central nervous system, bones, and semen. Animal studies have shown that ketoconazole can enter breast milk and cross the placenta. The estimated clearance of ketoconazole is 8.66 L/h. Ketoconazole is rapidly absorbed from the gastrointestinal tract. After oral administration, ketoconazole dissolves in gastric juice and is converted to hydrochloride before being absorbed by the stomach. The effect of food on the rate and extent of gastrointestinal absorption of ketoconazole is not well understood. Some clinicians have reported that taking ketoconazole on an empty stomach results in higher plasma drug concentrations than taking it with food. However, manufacturers indicate that taking it with food improves the absorption rate of ketoconazole and makes plasma drug concentrations more stable. Manufacturers believe that food improves its absorption rate by increasing the rate and/or extent of ketoconazole's dissolution (e.g., by increasing bile secretion) or delaying gastric emptying. Ketoconazole is a weak dibasic drug and therefore requires an acidic environment to dissolve and be absorbed. The bioavailability of oral ketoconazole depends on the pH of the gastric contents; elevated pH leads to reduced drug absorption. Reduced ketoconazole bioavailability has been reported in patients with acquired immunodeficiency syndrome (AIDS), possibly due to disease-related gastric acid deficiency. Concomitant administration of dilute hydrochloric acid solution can restore normal drug absorption in these patients. Drinking acidic beverages may increase the bioavailability of oral ketoconazole in some patients with gastric acid deficiency. For more complete data on the absorption, distribution, and excretion of ketoconazole (19 items), please visit the HSDB records page. Metabolites/Metabolites: The major metabolite of ketoconazole appears to be M2, the final product of the partial oxidation of imidazole. CYP3A4 is known to be a major participant in this reaction, with CYP2D6 also contributing. Other metabolites produced by the CYP3A4-mediated partial oxidation of imidazole include M3, M4, and M5. Ketoconazole can also undergo N-deacetylation to generate M14, alkyl oxidation to generate M7, N-oxidation to generate M13, aromatic hydroxylation to generate M8, or hydroxylation to generate M9. M9 can further undergo hydroxylation to generate M12, N-dealkylation to generate M10, followed by N-dealkylation to generate M15, or form an imine ion. Currently, no active metabolites are known, but the oxidative metabolites of M14 are associated with cytotoxicity. Ketoconazole is partially metabolized in the liver to several inactive metabolites via metabolic pathways including oxidation and degradation of the imidazole and piperazine rings, oxidative dealkylation, and aromatic hydroxylation. The elimination of ketoconazole is biphasic, with an initial phase half-life of 2 hours and a terminal half-life of 8 hours. The plasma concentration of ketoconazole decreases biphasically, with an initial phase half-life of approximately 2 hours and a terminal phase half-life of approximately 8 hours.
Plasma elimination is biphasic, with a half-life of 2 hours in the first 10 hours and 8 hours thereafter.

Toxicity Summary
Identification and Use: Ketoconazole is an antifungal drug. Human Exposure and Toxicity: Transient increases in serum AST, ALT, and alkaline phosphatase levels may occur during ketoconazole treatment. Severe hepatotoxicity, including fatal cases and cases requiring liver transplantation, has been reported in patients receiving oral ketoconazole. Hepatotoxicity can manifest as hepatocellular (most cases), cholestatic, or mixed damage. While ketoconazole-induced hepatotoxicity is usually reversible upon discontinuation, recovery can take months and, in rare cases, can lead to death. Symptomatic hepatotoxicity typically occurs within the first few months of ketoconazole treatment, but can sometimes occur within the first week. Some patients with ketoconazole-induced hepatotoxicity have no apparent risk factors for liver disease. Severe hepatotoxicity has been reported in patients receiving short-term high-dose oral ketoconazole as well as long-term low-dose oral ketoconazole. Many reported cases of hepatotoxicity have occurred in patients receiving this drug for onychomycosis (fungal nail infection) or for chronic refractory dermatophyte infections. Ketoconazole-induced hepatitis has been reported in some children. Ketoconazole at commonly used doses (200-400 mg daily) has been reported to transiently (lasting 2-12 hours) inhibit testosterone synthesis in the testes. Compensatory increases in serum luteinizing hormone (LH) concentrations may occur. A more persistent effect on testosterone synthesis has been reported at doses of 800-1200 mg daily; in a study of men receiving these higher doses, approximately 30% of patients in the 800 mg daily group and all patients in the 1200 mg daily group maintained serum testosterone concentrations below normal levels (below 300 ng/dL) throughout the day. Oligospermia, a condition characterized by reduced sperm count, often presents with decreased libido and impotence in these men, while azoospermia is rare. The drug appears to directly inhibit the synthesis of adrenal steroids and testosterone both in vitro and in vivo. The primary mechanism by which ketoconazole inhibits steroid synthesis appears to be through blocking multiple P-450 enzyme systems (e.g., 11β-hydroxylase, C-17,20-lyase, cholesterol side-chain lyase). Overall, these results indicate that many commonly used azole fungicides have endocrine-disrupting effects in vivo, although their mechanisms of action differ. Ketoconazole is known to have multiple endocrine-disrupting effects in humans. Animal studies: Oral administration resulted in sedation, rigidity, ataxia, tremors, convulsions, and, at doses >320 mg/kg, loss of righting reflex before death in mice, rats, and guinea pigs. Toxicity was also observed in dogs. Diarrhea and vomiting occurred at doses exceeding 80 mg/kg. Ketoconazole has been administered orally (gavage) and intravenously to mice, rats, guinea pigs, and dogs. Intravenous administration resulted in toxicity in rats, mice, and guinea pigs manifesting as convulsions, convulsions, and respiratory distress; mice, guinea pigs, and dogs showed loss of righting reflex before death. In dogs, toxicity was also manifested by licking and convulsions. In rats, except for a decrease in overall tumor incidence in female rats in the high-dose group, there were no significant differences in overall tumor incidence and type between the treatment and control groups. In rat developmental studies, the stillbirth rate in the 40 mg/kg dose group increased from 0.5% in the control group to 32.7%, and cannibalism was observed in both litters. In mice, sperm count was significantly reduced. Motility and density of the epididymal tail were observed. Fertility in ketoconazole-treated mice decreased sharply (50% were negative). Total protein and sialic acid content in the testes, epididymis, seminal vesicles, and ventral prostate were significantly reduced. Cholesterol content in the testes increased, while fructose content in the seminal vesicles decreased significantly. Ketoconazole treatment altered the biochemical environment of the reproductive tract. In rabbits, high doses (40 mg/kg/day) of ketoconazole exhibited maternal toxicity, embryotoxicity, and teratogenicity. Ketoconazole did not show any mutagenicity when assessed using the dominant lethal mutagenicity test or the Ames Salmonella microsomal activation test. Ecotoxicity studies: Ketoconazole induces the expression of CYP1A and CYP3A in rainbow trout. However, the most significant effect of ketoconazole is a 60% to 90% reduction in CYP3A catalytic activity in rainbow trout and killifish. Ketoconazole interacts with 14-α-demethylase, a cytochrome P-450 enzyme essential for the conversion of lanosterol to ergosterol. This leads to inhibition of ergosterol synthesis and increased fungal cell permeability. Other mechanisms may include inhibition of endogenous respiration, interaction with membrane phospholipids, inhibition of yeast mycelial transformation, inhibition of purine uptake, and impaired biosynthesis of triglycerides and/or phospholipids. Ketoconazole can also inhibit the synthesis of thromboxanes and sterols such as aldosterone, cortisol, and testosterone. (A1990, A1991, A1992, A1993)
Hepatotoxicity
Mild, transient elevation of liver enzymes: 4% to 20% of patients who take ketoconazole orally will experience abnormal liver function. These abnormalities are usually transient and asymptomatic, rarely requiring dose adjustment or discontinuation. Clinical hepatotoxicity caused by ketoconazole has been described in detail in the literature, with an estimated incidence of 1/2,000 to 1/15,000. Liver injury typically presents as acute hepatitis-like symptoms 1 to 6 months after the start of treatment. While most cases present with hepatocellular damage, cholestatic liver injury has also been reported. Rash, fever, eosinophilia, and autoantibody formation are rare. Recovery after discontinuation may be delayed, typically taking 1 to 3 months. Severe cases of acute liver failure, death, or requiring emergency liver transplantation have been reported.
Probability score: A (Etiology of clinical liver injury identified).
Use during pregnancy and lactation
◉ Use Overview During Lactation
Due to limited experience with the use of ketoconazole or levoketoconazole during lactation, and their potential to inhibit liver enzymes and cause hepatotoxicity, alternative medications are recommended as a first-line treatment. The manufacturer recommends that mothers taking ketoconazole or levonorgestrel avoid breastfeeding during treatment and for one day after the last dose. There is virtually no risk to breastfed infants from mothers using ketoconazole shampoo or topical medications. However, breastfeeding mothers should avoid applying the medication to their breasts or nipples, as the infant may ingest it, and safer alternatives are available. Only water-soluble creams or gels should be applied to the breasts, as ointments may expose the infant to high concentrations of mineral oil through licking. ◉ Effects on breastfed infants: One mother took 200 mg of ketoconazole orally for 10 days, and no adverse reactions were observed in her 1-month-old breastfed infant. ◉ Effects on breastfeeding and breast milk: As of the revision date, no relevant published information was found.

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Protein binding
Approximately 84% of ketoconazole binds to plasma albumin, and another 15% binds to blood cells, for a total plasma binding rate of 99%.

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Toxicity Data
Hepatotoxicity, LD50 = 86 mg/kg (oral in rats)
LD50: 44 mg/kg (intravenous in mice) (T66)
LD50: 702 mg/kg (oral in mice) (T66)

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Interactions
Since gastric acid is essential for the dissolution and absorption of ketoconazole, concomitant use with drugs that reduce gastric acid secretion or increase gastric pH should be avoided (e.g., antacids, anticholinergics, histamine H2 receptor antagonists, proton pump inhibitors, sucralfate, etc. may reduce ketoconazole absorption, leading to a decrease in the plasma concentration of the antifungal drug). Concomitant use of antacids, anticholinergics, histamine H2 receptor antagonists, proton pump inhibitors, etc., is not recommended in patients taking ketoconazole. Preparations (e.g., omeprazole, lanoprazole) or sucralfate.
It has been reported that patients taking ketoconazole experience elevated digoxin plasma concentrations. While it is unclear whether the concomitant use of ketoconazole causes these elevations, digoxin concentrations in patients taking this antifungal drug should be closely monitored.
Like other imidazole derivatives, ketoconazole may enhance the anticoagulant effect of coumarin anticoagulants. When ketoconazole is used in combination with these drugs, anticoagulation should be closely monitored and the dose adjusted accordingly.
In healthy adults, mefloquine (500 mg/dose)... When ketoconazole (400 mg once daily for 10 days) was used in combination with mefloquine (mg dose), the mean peak plasma concentration and AUC increased by 64% and 79%, respectively, and the mean elimination half-life increased from 322 hours to 448 hours. Due to the risk of potentially prolonged QT interval (QTc) and life-threatening complications, the mefloquine manufacturer states that ketoconazole should not be used in combination with mefloquine, nor should it be used within 15 weeks of the last dose of mefloquine. For more complete data on ketoconazole interactions (51 items in total), please visit the HSDB record page. Non-human toxicity values: Rat oral LD50 166 mg/kg; Rat intravenous LD50 86 mg/kg; Mouse oral LD50 618 mg/kg; Mouse intravenous LD50 41,500 ug/kg; Dog oral LD50 178 mg/kg. In vivo toxicity in mice: During the 56-day experiment, the body weight of mice in the ketoconazole group (200 mg/kg, administered by gavage for 7 days) was not significantly different from that in the control group (P>0.05). At the end of the experiment, HE staining showed no obvious pathological damage (such as hepatocyte necrosis and renal tubular damage) in the liver and kidney tissues of mice in the ketoconazole group. The serum liver function indicators (ALT, AST) and kidney function indicators (Cr, BUN) levels were not significantly different from those in the control group (P>0.05) [1]
2. In vitro cytotoxicity: The cytotoxicity of ketoconazole to HeLa cells was detected by reporter gene detection and MTT assay in hAR cells. When the concentration was as high as 20 μM, the cell survival rate remained above 90%, indicating that ketoconazole had no significant cytotoxicity to HeLa cells in this concentration range [2]

[1]. Effect of ketoconazole, a cytochrome P450 inhibitor, on the efficacy of quinine and halofantrine against Schistosoma mansoni in mice. Korean J Parasitol. 2013 Apr;51(2):165-75.

[2]. Eil C. Ketoconazole binds to the human androgen receptor. Horm Metab Res. 1992 Aug;24(8):367-70.

[3]. CYP24A1 inhibition enhances the antitumor activity of calcitriol. Endocrinology. 2010 Sep;151(9):4301-12.

[4]. High-throughput screening identified selective inhibitors of exosome biogenesis and secretion: A drug repurposing strategy for advanced cancer. Sci Rep. 2018 May 25;8(1):8161.

Therapeutic Uses
Antifungal Drugs Ketoconazole tablets should only be used when other effective antifungal therapies are ineffective or intolerable to the patient, and the potential benefit outweighs the potential risk. Ketoconazole tablets (Nizoral) are indicated for the treatment of the following systemic fungal infections, especially in patients who have not responded to or are intolerant of other therapies: blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. Ketoconazole tablets should not be used for fungal meningitis because it has poor penetration into the cerebrospinal fluid. /US Product Label Includes/ Oral ketoconazole has been used for the palliative treatment of Cushing's syndrome (hypercortisolemia), including hyperadrenocorticism associated with adrenal or pituitary adenomas or ectopic adrenocorticotropic hormone-secreting tumors. Based on its endocrine effects, this drug has been used to treat advanced prostate cancer. The safety and efficacy of ketoconazole for these two indications have not been established. Oral ketoconazole has also been used to treat hypercalcemia in patients with sarcoidosis, as well as tuberculosis-associated hypercalcemia and idiopathic infantile hypercalcemia and hypercalciuria. /Not included on US product label/
Ketoconazole has been used to treat sporotrichosis caused by Sporothrix schenckii; however, it is not recommended due to its poor efficacy and more adverse reactions than some other azole drugs. Oral itraconazole is considered the first-line treatment for cutaneous, lymphocutaneous, or mild pulmonary or osteoarticular sporotrichosis, and can also be used as a follow-up treatment for more severe infections after effective treatment with intravenous amphotericin B. /Not included on US product label/
For more complete data on the therapeutic uses of ketoconazole (18 types), please visit the HSDB record page.

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Drug Warning
/Black Box Warning/ Warning: Ketoconazole tablets should only be used when other effective antifungal therapies are unavailable or intolerable, and the potential benefits outweigh the potential risks. Hepatotoxicity: Serious hepatotoxicity, including cases of death or requiring liver transplantation, has been reported with oral ketoconazole. Some patients do not have obvious risk factors for liver disease. Patients receiving this medication should be informed of the risks by their physician and closely monitored. QT Interval Prolongation and Drug Interactions Leading to QT Interval Prolongation: Ketoconazole is contraindicated with the following drugs: dofetilide, quinidine, pimozide, cisapride, methadone, disopyramide, dronedarone, and ranolazine. Ketoconazole can cause elevated plasma concentrations of these drugs and may prolong the QT interval, sometimes even leading to life-threatening ventricular arrhythmias such as torsades de pointes. Transient increases in serum AST, ALT, and alkaline phosphatase levels may occur during ketoconazole treatment. Serious hepatotoxicity, including cases of death or requiring liver transplantation, has been reported in patients receiving oral ketoconazole. Hepatotoxicity can manifest as hepatocellular (in most cases), cholestatic, or mixed damage. Although ketoconazole-induced hepatotoxicity is usually reversible upon discontinuation, recovery can take months and, in rare cases, can lead to death. Symptomatic hepatotoxicity typically occurs within the first few months of ketoconazole treatment, but can sometimes occur within the first week. Some patients with ketoconazole-induced hepatotoxicity have no apparent risk factors for liver disease. Severe hepatotoxicity has been reported in patients taking high-dose oral ketoconazole for short periods and low-dose oral ketoconazole for long periods. Many reported cases of hepatotoxicity have occurred in patients receiving this drug to treat onychomycosis (tinea unguium) or chronic refractory dermatophyte infections. Ketoconazole-induced hepatitis has been reported in some children. Ketoconazole tablets are contraindicated for use with several CYP3A4 substrates, such as dofetilide, quinidine, cisapride, and pimozide. Concomitant use with ketoconazole can lead to increased plasma concentrations of these drugs and may increase or prolong therapeutic effects and adverse reactions, potentially resulting in serious adverse events. For example, elevated plasma concentrations of certain such drugs can lead to QT interval prolongation, which can sometimes result in life-threatening ventricular arrhythmias, including torsades de pointes (a potentially fatal arrhythmia). In addition, the following drugs are contraindicated with ketoconazole tablets: methadone, disopyramide, dronedarone, ergot alkaloids (such as dihydroergotamine, ergonovine, ergotamine, methylergonovine), irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisodipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin, and colchicine. Ketoconazole tablets are contraindicated in patients with acute or chronic liver disease. For more complete data on drug warnings for ketoconazole (46 in total), please visit the HSDB records page.

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Pharmacodynamics
Ketoconazole, like other azole antifungal drugs, is a bacteriostatic agent that can inhibit the growth of fungal cells, thereby preventing the growth and spread of fungi in the body.

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1. Mechanism of action and drug interaction Ketoconazole: As a CYP enzyme inhibitor, ketoconazole enhances its anti-schistosomiasis efficacy by inhibiting the metabolism of quinine and halofantrolin in mice and increasing their concentration in blood and tissues. Experiments have shown that when ketoconazole is used in combination with quinine or halofantrolin, the toxicity is not significantly increased, suggesting that this combination therapy has potential application value in anti-schistosomiasis treatment [1]
2. Mechanism of action of ketoconazole against androgens: Ketoconazole binds directly to the human androgen receptor (hAR) and competitively inhibits the binding of endogenous androgens (such as dihydrotestosterone, DHT) to hAR, thereby inhibiting the transcriptional activity of hAR and reducing the expression of androgen target genes. This mechanism provides experimental evidence for the use of ketoconazole in androgen-dependent diseases such as prostate cancer and acne, especially when androgen levels cannot be lowered by surgery or other methods, ketoconazole can serve as an alternative anti-androgen therapy [2]

C26H28CL2N4O4

531.4309

530.148

C, 58.76; H, 5.31; Cl, 13.34; N, 10.54; O, 12.04

65277-42-1

(+)-Ketoconazole;142128-59-4;(-)-Ketoconazole;142128-57-2;Ketoconazole-d8;1217706-96-1;Ketoconazole-d4;1398065-75-2

456201

White to off-white solid powder

1.4±0.1 g/cm3

753.4±60.0 °C at 760 mmHg

146°C

409.4±32.9 °C

0.0±2.5 mmHg at 25°C

1.642

3.55

69.06

0

6

7

36

735

2

CC(=O)N1CCN(CC1)C2=CC=C(C=C2)OC[C@H]3CO[C@](O3)(CN4C=CN=C4)C5=C(C=C(C=C5)Cl)Cl

XMAYWYJOQHXEEK-OZXSUGGESA-N

InChI=1S/C26H28Cl2N4O4/c1-19(33)31-10-12-32(13-11-31)21-3-5-22(6-4-21)34-15-23-16-35-26(36-23,17-30-9-8-29-18-30)24-7-2-20(27)14-25(24)28/h2-9,14,18,23H,10-13,15-17H2,1H3/t23-,26-/m0/s1

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

Ketoconazole; Nizoral, Kuric, (+)-Ketoconazole; 65277-42-1; 142128-59-4; (2R,4S)-ketoconazole; Kuric; MFCD00058579; Fungoral, Ketoderm; Xolegel, Extina

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: 2.5 mg/mL (4.70 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (4.70 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (4.70 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 30% propylene glycol, 5% Tween 80, 65% D5W: 30mg/mL

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。