生物活性

• 描述Calcium-sensing receptor (CaSR), which belongs to the G protein-coupled receptor superfamily, is responsible for the regulation of systemic Ca²⁺ metabolism. Cinacalcet hydrochloride is a calcimimetic that allosterically increases the sensitivity and responsiveness of CaSR to Ca²⁺. It activates the wild-type CaSR signaling in cellular proliferation and PI hydrolysis assays with pEC₅₀ values of 7.6 and 7.3, respectively^[1]. When primary cultured human parathyroid cells were incubated with 0.5 mM extracellular Ca²⁺, cinacalcet hydrochloride from 0 – 1000 nM additionally suppressed the secretion of parathyroid hormone at a dose-dependent manner^[2]. Cinacalcet hydrochloride at 30 – 1000 nM had no effect on osteoclastic formation or resorption in osteoclastic cells cultured in calcium-containing medium with the concentration of 1.6 or 6.1 mM^[3]. Oral administration of primary hyperparathyroidism mice with 1 mg/g cinacalcet hydrochloride for 10 days led to significantly reduced levels of parathyroid and Ca in serum. The uptake of 5-Bromo-2'-deoxyuridine was also significantly decreased in mice following the administration of cinacalcet hydrochloride compared to the untreated ones^[4].
• 作用机制Cinacalcet hydrochloride cooperates with Ca²⁺ to activate CaSR via interacting with its transmembrane domain^[1].

• 动物研究
  剂量	Rat: 1 mg/kg - 10 mg/kg[5] (p.o.); 0.1 mg/kg - 10 mg/kg[1] (s.c.) Mice: 10 mg/kg - 100 mg/kg (p.o.)
  给药途径	p.o., s.c.
  动物药代数据	Animal Rats[6] Monkeys[6] Dose 1 mg/kg 10 mg/kg Administration i.v. or p.o. p.o. T1/2 5.5 h (i.v.) 3.1 h (p.o.) 9.1 h Tmax 1.9 h (p.o.) 2.8 h CL 1.00 L/h/kg (i.v.) AUC 1570 ng·h/ml (i.v.) 21.5 ng·h/ml (p.o.) 237.1 ng·h/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
  NCT01100723	-	-	Completed	-	-
  NCT02464072	Hyperparathyroidism, Secondary	Not Applicable	Active, not recruiting	July 2019	Brazil ... more >> University of Sao Paulo General Hospital Sao Paulo, SP, Brazil Collapse <<
  NCT01073462	-	-	Completed	-	Austria ... more >> Site Reference ID/Investigator# 27447 Graz, Austria, 8010 Site Reference ID/Investigator# 49182 Graz, Austria, 8020 Site Reference ID/Investigator# 27483 Graz, Austria, 80360 Site Reference ID/Investigator# 52742 Graz, Austria, 8052 Site Reference ID/Investigator# 27487 Innsbruck, Austria, 6020 Site Reference ID/Investigator# 36983 Linz, Austria, 4010 Site Reference ID/Investigator# 27484 Linz, Austria, 4020 Site Reference ID/Investigator# 27485 Rottenmann, Austria, 8786 Site Reference ID/Investigator# 27446 Vienna, Austria, 1030 Site Reference ID/Investigator# 53469 Vienna, Austria, 1090 Site Reference ID/Investigator# 27482 Vienna, Austria, 1130 Site Reference ID/Investigator# 10981 Vienna, Austria, 1220 Collapse <<

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• 参考文献

• [1] Ma JN, Owens M, et al. Characterization of highly efficacious allosteric agonists of the human calcium-sensing receptor. J Pharmacol Exp Ther. 2011;337(1):275-84.

  [2] Kawata T, Imanishi Y, et al. Direct in vitro evidence of the suppressive effect of cinacalcet HCl on parathyroid hormone secretion in human parathyroid cells with pathologically reduced calcium-sensing receptor levels. J Bone Miner Metab. 2006;24(4):300-6.

  [3] Shalhoub V, Grisanti M, et al. In vitro studies with the calcimimetic, cinacalcet HCl, on normal human adult osteoblastic and osteoclastic cells. Crit Rev Eukaryot Gene Expr. 2003;13(2-4):89-106.

  [4] Imanishi Y, Kawata T, et al. Cinacalcet HCl suppresses Cyclin D1 oncogene-derived parathyroid cell proliferation in a murine model for primary hyperparathyroidism. Calcif Tissue Int. 2011;89(1):29-35.

  [5] Colloton M, Shatzen E, et al. Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism. Kidney Int. 2005 Feb;67(2):467-76.

  [6] Cinacalcet HCl

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