生物活性

• 靶点	JAK3 IC50:1nM

• 描述Tofacitinib Citrate is the citrate form of Tofacitinib. Tofacitinib is an ATP-competed inhibitor of JAK with IC50 values of 3.2±1.4 nM, 4.1±0.4 nM, 1.6±0.2 nM, 34.0±6.0 nM for JAK1, JAK2, JAK3 and TYK2 in in vitro enzyme assays. It competes with ATP for binding to the active site of the kinase domain of JAKs with Ki values of 0.68 ± 0.12 nM (JAK1), 0.99 ± 0.04 nM (JAK2), 0.24 ± 0.02 nM (JAK3) and 4.39 ± 0.27 nM (TYK2). Tofacitinib potently inhibits multiple cytokine activated JAK/STAT signaling pathways in normal human, mouse or rat whole blood with IC50s below 200 nM. Selectivity assessed in mouse and rat whole blood shows that tofacitinib appears to be more potently to JAK1 and JAK3. In cell assays, tofacitinib inhibits human total myeloid and CFU-G colony formation with IC50s of 0.87 and 0.93 μM. In AIA rats, tofacitinib treatment can decrease paw volume and disease-elevated neutrophil count to normal range compared to vehicle treated control rats. Tofacitinib treatment also dose-dependently decreased both IL-17 and IL-6 of the AIA-induced increase compared to control levels with an approximately 80% inhibition. It significantly inhibits the AIA-induced increase in maturing myeloid cells by approximately 50% at the 10 mg/kg dose^[6]. Tofacitinib has been approved by the U.S. Food and Drug Administration and European Medicines Agency for the treatment of rheumatoid arthritis (RA), psoriatic arthritis and ulcerative colitis^[2].
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  CD4+ T	20/100/500 nM	Function Assay	48 h	inhibits the levels of IL-4, IFN-γ, IL-17A and IL-22	21884580
  CD4+ T	100/500 nM	Growth Inhibition Assay	48 h	inhibits anti-CD3-induced CD4+ T cell proliferation	21884580
  CD4+ T	100 nM	Function Assay	24/48 h	abrogates CD3-induced phosphorylation of STATs	21884580

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• 动物研究
  剂量	Rat: 5 mg/kg - 50 mg/kg[3] (i.v.), 10 mg/kg - 100 mg/kg[4] (p.o.) Mice: 1 mg/kg - 100 mg/kg[5] (p.o.)
  给药途径	i.v., p.o.
  动物药代数据	Animal Rats[4] Dogs[4] Monkeys[4] Dose 3 mg/kg or 10 mg/kg (i.v.) 10 mg/kg (p.o., water) 3 mg/kg (i.v.) 5 mg/kg (p.o., 0.5% methylcellulose) 3 mg/kg (i.v.) 5 mg/kg (p.o., 0.5% methylcellulose) Administration i.v. p.o. i.v. p.o. i.v. p.o. F 43.3% (p.o.) 43.0% (p.o.) 48.0% (p.o.) T1/2 0.6 ± 0.1 h (i.v.) 2.0 ± 1.5 h (p.o.) 1.2 ± 0.1 h (i.v.) 2.1 ± 0.4 h (i.v.) Tmax 0.3 ± 0.1 h (p.o.) 0.5 ± 0.4 h (p.o.) 1.1 ± 0.9 h (p.o.) CL 62 ± 14 ml/min/kg (i.v.) 19 ± 10 ml/min/kg (i.v.) 18 ± 4 ml/min/kg (i.v.) Cmax 2400 ± 948 ng/ml (p.o.) 1020 ± 255 ng/ml (p.o.) 791 ± 157 ng/ml (p.o.) AUC0→∞ 840 ± 184 ng·h/ml (i.v.) 2770 ± 837 ng·h/ml (p.o.) 3250 ± 1610 ng·h/ml (i.v.) 2330 ± 423 ng·h/ml (p.o.) 2850 ± 543 ng·h/ml (i.v.) 2280 ± 338 ng·h/ml (p.o.) Vss 2.6 ± 1.3 L/kg (i.v.) 1.8 ± 0.8 L/kg (i.v.) 1.7 ± 0.2 L/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
  NCT01023100	Arthritis, Rheumatoid	Phase 1	Completed	-	United States, Massachusetts ... more >> Pfizer Investigational Site Woburn, Massachusetts, United States, 01801 Collapse <<
  NCT01101919	Healthy	Phase 1	Completed	-	China ... more >> Pfizer Investigational Site Beijing, China, 100032 Collapse <<
  NCT01246583	Psoriasis	Phase 2	Completed	-	United States, Alabama ... more >> Pfizer Investigational Site Mobile, Alabama, United States, 36606 United States, California Pfizer Investigational Site Los Angeles, California, United States, 90045 United States, Florida Pfizer Investigational Site Orange Park, Florida, United States, 32073 United States, Nebraska Pfizer Investigational Site Omaha, Nebraska, United States, 68144 United States, New Mexico Pfizer Investigational Site Albuquerque, New Mexico, United States, 87106 United States, South Dakota Pfizer Investigational Site Rapid City, South Dakota, United States, 57702 United States, Texas Pfizer Investigational Site Dallas, Texas, United States, 75231 Canada, Ontario Pfizer Investigational Site Waterloo, Ontario, Canada, N2J 1C4 Canada, Quebec Pfizer Investigational Site Montreal, Quebec, Canada, H2K 4L5 Pfizer Investigational Site Montreal, Quebec, Canada, H3Z 2S6 Canada Pfizer Investigational Site Quebec, Canada, G1V 4X7 Collapse <<

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• 参考文献

• [1] Meyer DM, Jesson MI, et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm (Lond). 2010 Aug 11;7:41.

  [2] Meyer DM, Jesson MI, Li X, Elrick MM, Funckes-Shippy CL, Warner JD, Gross CJ, Dowty ME, Ramaiah SK, Hirsch JL, Saabye MJ, Barks JL, Kishore N, Morris DL. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm (Lond). 2010 Aug 11;7:41. doi: 10.1186/1476-9255-7-41. PMID: 20701804; PMCID: PMC2928212.

  [3] Lee JS, Kim SH, et al. Dose-Dependent Pharmacokinetics of Tofacitinib in Rats: Influence of Hepatic and Intestinal First-Pass Metabolism. Pharmaceutics. 2019 Jul 5;11(7). pii: E318.

  [4] Tofacitinib

  [5] Xeljanz

  [6] Lloyd-Lavery A. Long-term safety data for tofacitinib, an oral Janus kinase inhibitor, for the treatment for psoriasis. Br J Dermatol. 2018 Oct;179(4):815-816. doi: 10.1111/bjd.17016. PMID: 30318813.

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