生物活性

• 靶点	CYP3A IC50:0.22mM

• 描述Ketoconazole, an imidazole anti-fungal agent, has often produced features of androgen deficiency including decreased libido, gynecomastia, impotence, oligospermia, and decreased testosterone levels, in men being treated for chronic mycotic infections^[6]. It also inhibits arachidonic acid lipoxygenases and cytochrome P-450 enzymes^[7]. Ketoconazole competed with [³H]methyltrienolone (R1881) for androgen binding sites in dispersed, intact cultured human skin fibroblasts^[6]. In the serum independent HT29-S-B6 colon cell clone, ketoconazole reduced cell proliferation and [³H]thymidine incorporation in a dose-dependent fashion, with a 50% inhibitory concentration of approximately 2.5 μM. It also inhibited [³H]thymidine incorporation in the hormone-independent breast cancer cells MDA-MB-231 and Evsa-T, with respective 50% inhibitory concentration of approximately 13 and 2 μM. In addition, ketoconazole induced a dose-dependent decrease of the number of cells in S phase within 24 h of treatment (from 17 to 3%) and a corresponding increase of the percentage of cells in Go-G1 (from 64 to 80%)^[7]. All strains of the seven Malassezia species were susceptible to ketoconazole at low concentrations. M. furfur, M. sympodialis, M. slooffiae, M. pachydermatis, M. globosa, M. obtusa and M. restricta were most sensitive to it with minimum inhibitory concentrations (MICs) ranging from < or = 0.03 to 0.125 μg/mL^[8]. Pretreatment with ketoconazole (25 mg/kg, i.p.) significantly decreased plasma corticosterone and reduced low dose (i.e. 0.125 - 0.25 mg/kg per infusion) cocaine self-administration without affecting food-reinforced responding^[9]. Ketoconazole raised the AUC of orally administered digoxin from 63 ± 17 to 411 ± 50 μg•h/l. When given intravenously, digoxin AUC increased from 93 ± 22 to 486 ± 26 μg•h/l with ketoconazole administration^[10].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  CHO cells	-	Function assay	-	Inhibition of CYP24A1 expressed in CHO cells, IC50=0.52 μM	20655626
  CHO cells	-	Function assay	-	Inhibition of human ERG expressed in CHO cells by whole cell patch clamp technique, IC50=1.90546 μM	18448342
  hamster V79MZh11B1 cells	-	Function assay	-	Inhibition of human CYP11B1 expressed in hamster V79MZh11B1 cells, IC50=0.127 μM	18672868

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• 动物研究
  剂量	Swiss mice: 25 mg/kg - 200 mg/kg[3] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Rats[4] Monkeys[5] Dose 5 mg 0.98 ± 0.07 mg/kg Administration intraduodenal administration i.v. MRT 159.7 ± 60.2 h T1/2 92.8 ± 50.4 h 50.6 ± 6.5 min Tmax 70.0 ± 14.1 min 53.3 ± 12.0 min CL 12.5 ± 1.2 ml/min/kg Cmax 16.4 ± 5.1 μg/ml 961 ± 20 ng/ml Vdss 0.661 ± 0.119 L/kg DNAUC 80.1 ± 7.1 min·kg/l CL/F 1.6 ± 0.8 ml/min AUC 3679 ± 1894 μg·h/ml 78.4 ± 9.8 min·μg/ml

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT00238225	Unspecified Adult Solid Tumor,... more >> Protocol Specific Collapse <<	Phase 1	Completed	-	United States, New York ... more >> Roswell Park Cancer Institute Buffalo, New York, United States, 14263-0001 Collapse <<
  NCT00019695	Stage IV Prostate Cancer ... more >> Bone Metastases Adenocarcinoma of the Prostate Recurrent Prostate Cancer Collapse <<	Phase 2	Terminated	-	United States, Maryland ... more >> Medicine Branch Bethesda, Maryland, United States, 20892 Collapse <<
  NCT00931073	Alzheimer's Disease ... more >> Huntington's Disease Collapse <<	Phase 1	Completed	-	United States, Michigan ... more >> Pfizer Investigational Site Kalamazoo, Michigan, United States, 49007 Collapse <<

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• 参考文献

• [1] Oliver WR Jr, Shenk JL, et al. A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5306-11.

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

  [3] Awasthi A, Dutta GP, et al. Resistance reversal action of ketoconazole against mefloquine resistance of Plasmodium yoelii nigeriensis. Exp Parasitol. 2004 Jul-Aug;107(3-4):115-9.

  [4] Saadeddin A, Peris JE, et al. Pharmacokinetic interaction between efavirenz and ketoconazole in rats. Xenobiotica. 2009 Feb;39(2):135-9.

  [5] Ward KW, Stelman GJ, et al. Development of an in vivo preclinical screen model to estimate absorption and first-pass hepatic extraction of xenobiotics. II. Use of ketoconazole to identify P-glycoprotein/CYP3A-limited bioavailability in the monkey. Drug Metab Dispos. 2004 Feb;32(2):172-7.

  [6] Eil C. Ketoconazole binds to the human androgen receptor. Horm Metab Res. 1992 Aug;24(8):367-70. doi: 10.1055/s-2007-1003337. PMID: 1526623.

  [7] Forgue-Lafitte ME, Coudray AM, Fagot D, Mester J. Effects of ketoconazole on the proliferation and cell cycle of human cancer cell lines. Cancer Res. 1992 Dec 15;52(24):6827-31. PMID: 1458471.

  [8] Gupta AK, Kohli Y, Li A, Faergemann J, Summerbell RC. In vitro susceptibility of the seven Malassezia species to ketoconazole, voriconazole, itraconazole and terbinafine. Br J Dermatol. 2000 Apr;142(4):758-65. doi: 10.1046/j.1365-2133.2000.03294.x. PMID: 10792228.

  [9] Goeders NE, Peltier RL, Guerin GF. Ketoconazole reduces low dose cocaine self-administration in rats. Drug Alcohol Depend. 1998 Dec 1;53(1):67-77. doi: 10.1016/s0376-8716(98)00108-2. PMID: 10933341.

  [10] Salphati L, Benet LZ. Effects of ketoconazole on digoxin absorption and disposition in rat. Pharmacology. 1998 Jun;56(6):308-13. doi: 10.1159/000028214. PMID: 9654217.

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