生物活性

• 描述5 alpha Reductases (5ARs) are important enzymes for the progression of benign prostatic hyperplasia by converting testosterone to dihydrotestosterone with 2 isoenzymes. Dutasteride is a competitive inhibitor of 5ARs with IC50 value of 6 nM for type-1 5-AR and 7 nM for type-2 5-AR. In a study, 1879 BPH patients were treated with 0.5 mg dutasteride daily or combined treated with other drugs like tamsulosin and alfuzosin. The results found that IPSS score point was meanly reduced about 6.5-point. The adverse events in the dutasteride group was not statistically significant with OR 1.10.^[1] Dutasteride is 60-fold more potential towards type 1 5AR and also is most potent dual 5AR inhibitor. In a male rats model of prostate growth, daily treated them with dutasteride at 1, 10, or 100 mg/kg found no significant difference between these dose groups, indicating that a stronger potent when the maximum effect in this model achieved at 1 mg/kg/day. In the rats model, the half-life, total body clearance, volume at steady-state and oral bioavailability of 1 mg/kg/day dutasteride were 13.7 hr, 4.1 mL/min/kg, 4 L/kg and 100% respectively. While in dog model with oral administration of 5 mg/kg dutasteride, these values were 65 hr, 0.5 mL/min/kg, 3L/kg and 43% respectively. Dutasteride doses of 0.01 to 40 mg were studied iin some Phase I studies, the results showed that the absolute bioavailability ranged from 40-100% as well as production of a dose related decrease in DHT. No effect when single oral doses < 0.1 mg while significantly decreasing of DHT when oral dutasteride doses > 5 mg. The peak decreasing was 95% at concentration of 40 mg. Furthermore, dutasteride doses of 0.1, 0.5, 2.5, 2.5 and 5 mg were studied in 53 BPH patients, >=95% decreasing of DHT was observed at doses of 2.5mg/day and up.^[2]
• 作用机制Dutasteride-5α reductase is a stable complex with a slow dissociation rate, thereby preventing the enzymes from binding to testosterone.^[3]

• 动物研究
  剂量	Mice: 5 mg/kg, 12.5 mg/kg[4] (i.p., SID)
  给药途径	i.p.
  动物药代数据	Animal Rats[5] Dose 2.5 mg/kg (i.v.) 5 mg/kg (p.o.) Administration i.v. p.o. AUCinf 1148 ± 81 μg·min/ml (i.v.) T1/2 1607 ± 196 min (i.v.) Tmax 60 min (p.o.) AUClast 275 ± 9 μg·min/ml (p.o.) CL 2.19 ± 0.16 ml/min/kg (i.v.) Cmax 289 ± 10 ng/ml (p.o.) Vss 4900 ± 326 ml/kg (i.v.)

• 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
  NCT02147964	Gonadotropin Deficiency	Phase 2	Not yet recruiting	December 2026	United States, Washington ... more >> University of Washington Medical Center (Health Sciences) Not yet recruiting Seattle, Washington, United States, 98195 Contact: Iris Nielsen    206-221-5473    nielseni@uw.edu    Contact: Kathy Winter    206-616-0484    klwinter@uw.edu    Principal Investigator: Mara Roth, MD          Sub-Investigator: John Amory, MD, MPH          Sub-Investigator: Stephanie Page, MD, PhD          Sub-Investigator: Bradley Anawalt, MD Collapse <<
  NCT00298155	-	-	Completed	-	-
  NCT00298155	Cancer Prosta... more >>te Neoplasms Collapse <<	Phase 2	Completed	-	United States, Washington ... more >> Veterans' Administration Puget Sound Health Care System (VAPSHCS) Seattle, Washington, United States, 98108-1532 University of Washington Seattle, Washington, United States, 98195-6158 Collapse <<

• 更多
• 参考文献

• [1] Jun JEJ, Kinkade A, et al. 5α-Reductase Inhibitors for Treatment of Benign Prostatic Hyperplasia: A Systematic Review and Meta-Analysis. Can J Hosp Pharm. 2017;70(2):113-119.

  [2] Frye SV. Discovery and clinical development of dutasteride, a potent dual 5alpha-reductase inhibitor. Curr Top Med Chem. 2006;6(5):405-21.

  [3] Vitalis OO, Christopher CO. The Role of Dutasteride in Acute Prostatic Haematuria. 2017 Nov Vol.8 No.11.

  [4] Litim N, Bourque M, et al. The 5α-reductase inhibitor Dutasteride but not Finasteride protects dopamine neurons in the MPTP mouse model of Parkinson's disease. Neuropharmacology. 2015 Oct;97:86-94.

  [5] Seo SW, Park JW, et al. In Vitro and In Vivo Assessment of Metabolic Drug Interaction Potential of Dutasteride with Ketoconazole. Pharmaceutics. 2019 Dec 11;11(12). pii: E673.

• 更多

• Collapse