生物活性

• 靶点	Androgen Receptor Ki:55nM

• 描述The androgen receptor (AR) and the androgen-AR signaling pathway play a significant role in male sexual differentiation and the development and function of male reproductive and non-reproductive organs ^[7]. Flutamide, mainly used in the treatment of prostate cancer, is an antiandrogenic drug. Flutamida-OH is the active metabolite form of Flutamide and directly binds to the androgen receptor with K_i of 55 nM. In rat adenohypophysial cells in primary culture, the specific uptake of [³H] testosterone (T) is completely blocked by increasing concentrations of the pure antiandrogen flutamide-OH at an IC₅₀ value of 50 nM ^[8]. In adult male rats, Treatment for 10 days with flutamide (5 mg/rat, twice daily) caused a marked stimulation of plasma testosterone (T) associated with a significant increase in plasma gonadotropin concentrations and inhibited plasma prolactin (PRL) levels. Moreover, flutamide treatment alone produces an important inhibition of ventral prostate and seminal vesicle weights associated with a significant decrease in prostatic beta-adrenergic receptor levels ^[9].

• 动物研究
  剂量	Mice: 6.6 mg/kg, 33 mg/kg[3] (s.c.); 60 mg/kg[4] (i.p.) Rat: 50 mg/kg - 200 mg/kg[5] (p.o.); 12 mg/kg[6] (i.v.)
  给药途径	s.c., i.p.
  动物药代数据	Animal Rats[6] Dose 12 mg/kg Administration i.v. AUCinf 7.97 ± 0.22 μg·h/ml Vd 2.31 ± 0.1 L/kg T1/2 0.88 ± 0.02 h Tmax 0.25 ± 0.02 h CL 1.51 ± 0.2 L/h/kg Cmax 7.10 ± 0.5 μg/ml MRTinf 1.19 ± 0.2 h

• 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
  NCT00850941	-	-	Active, not recruiting	January 2021	United States, New Mexico ... more >> Kaseman Presbyterian Hospital Albuquerque, New Mexico, United States, 87110 United States, South Carolina Spartanburg Regional Healthcare System Spartanburg, South Carolina, United States, 29303 United States, Texas University of Texas MD Anderson Cancer Center Houston, Texas, United States, 77030 Collapse <<
  NCT00003653	Prostate Cancer	Phase 3	Completed	-	Canada, Alberta ... more >> Tom Baker Cancer Centre Calgary, Alberta, Canada, T2N 4N2 Cross Cancer Institute Edmonton, Alberta, Canada, T6G 1Z2 Canada, British Columbia BCCA - Cancer Centre for the Southern Interior Kelowna, British Columbia, Canada, V1Y 5L3 BCCA - Fraser Valley Cancer Centre Surrey, British Columbia, Canada, V3V 1Z2 Clinical Research Unit at Vancouver Coastal Vancouver, British Columbia, Canada, V5Z 1M9 BCCA - Vancouver Cancer Centre Vancouver, British Columbia, Canada, V5Z 4E6 Canada, Manitoba CancerCare Manitoba Winnipeg, Manitoba, Canada, R3E 0V9 Canada, New Brunswick The Vitalite Health Network - Dr. Leon Richard Moncton, New Brunswick, Canada, E1C 8X3 Atlantic Health Sciences Corporation Saint John, New Brunswick, Canada, E2L 4L2 Canada, Newfoundland and Labrador Dr. H. Bliss Murphy Cancer Centre St. John's, Newfoundland and Labrador, Canada, AIB 3V6 Canada, Nova Scotia QEII Health Sciences Center Halifax, Nova Scotia, Canada, B3H 1V7 Canada, Ontario William Osler Health Centre, Brampton Memorial Brampton, Ontario, Canada, L6R 3J7 Juravinski Cancer Centre at Hamilton Health Sciences Hamilton, Ontario, Canada, L8V 5C2 Cancer Centre of Southeastern Ontario at Kingston Kingston, Ontario, Canada, K7L 5P9 London Regional Cancer Program London, Ontario, Canada, N6A 4L6 Credit Valley Hospital Mississauga, Ontario, Canada, L5M 2N1 Ottawa Health Research Institute - General Division Ottawa, Ontario, Canada, K1H 8L6 Niagara Health System St. Catharines, Ontario, Canada, L2R 7C6 Northeast Cancer Center Health Sciences Sudbury, Ontario, Canada, P3E 5J1 Thunder Bay Regional Health Science Centre Thunder Bay, Ontario, Canada, P7B 6V4 Odette Cancer Centre Toronto, Ontario, Canada, M4N 3M5 Univ. Health Network-Princess Margaret Hospital Toronto, Ontario, Canada, M5G 2M9 Windsor Regional Cancer Centre Windsor, Ontario, Canada, N8W 2X3 Canada, Quebec CHUM - Hopital Notre-Dame Montreal, Quebec, Canada, H2L 4M1 McGill University - Dept. Oncology Montreal, Quebec, Canada, H2W 1S6 CHUQ-Pavillon Hotel-Dieu de Quebec Quebec City, Quebec, Canada, G1R 2J6 Centre hospitalier universitaire de Sherbrooke Sherbrooke, Quebec, Canada, J1H 5N4 Canada, Saskatchewan Allan Blair Cancer Centre Regina, Saskatchewan, Canada, S4T 7T1 Saskatoon Cancer Centre Saskatoon, Saskatchewan, Canada, S7N 4H4 Collapse <<
  NCT00003517	Adenocarcinoma of the Prostate... more >> Stage III Prostate Cancer Stage IV Prostate Cancer Recurrent Prostate Cancer Collapse <<	Phase 2	Withdrawn	-	United States, Texas ... more >> Burzynski Clinic Houston, Texas, United States, 77055-6330 Collapse <<

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• 参考文献

• [1] Luthy IA, Begin DJ, Labrie F. Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture. J Steroid Biochem. 1988 Nov;31(5):845-52.

  [2] Simard J, Luthy I, et al. Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues. Mol Cell Endocrinol. 1986 Mar;44(3):261-70.

  [3] Raghow S, Kuliyev E, et al. Efficacious chemoprevention of primary prostate cancer by flutamide in an autochthonous transgenic model. Cancer Res. 2000 Aug 1;60(15):4093-7.

  [4] Pu Y, Xu M, et al. Androgen receptor antagonists compromise T cell response against prostate cancer leading to early tumor relapse. Sci Transl Med. 2016 Apr 6;8(333):333ra47.

  [5] Wang HX, Liu X, et al. Induction of liver cytochrome P450 1A2 expression by flutamide in rats. Acta Pharmacol Sin. 2005 Nov;26(11):1382-6.

  [6] Elzoghby AO, Helmy MW, et al. Novel ionically crosslinked casein nanoparticles for flutamide delivery: formulation, characterization, and in vivo pharmacokinetics. Int J Nanomedicine. 2013;8:1721-32.

  [7] Shukla GC, Plaga AR, Shankar E, Gupta S. Androgen receptor-related diseases: what do we know? Andrology. 2016 May;4(3):366-81. doi: 10.1111/andr.12167. Epub 2016 Mar 16. PMID: 26991422.

  [8] Simard J, Luthy I, Guay J, Bélanger A, Labrie F. Characteristics of interaction of the antiandrogen flutamide with the androgen receptor in various target tissues. Mol Cell Endocrinol. 1986 Mar;44(3):261-70. doi: 10.1016/0303-7207(86)90132-2. PMID: 3956856.

  [9] Marchetti B, Labrie F. Characteristics of flutamide action on prostatic and testicular functions in the rat. J Steroid Biochem. 1988 Jun;29(6):691-8. doi: 10.1016/0022-4731(88)90170-7. PMID: 2838689.

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