Pharmaceuticals Research Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., 363 Shiosaki, Hokusei-cho, Inabe, Mie, 511-0406, Japan.
Pharmaceuticals Research Laboratories, Sanwa Kagaku Kenkyusho Co., Ltd., 363 Shiosaki, Hokusei-cho, Inabe, Mie, 511-0406, Japan.
Eur J Pharmacol. 2023 Oct 5;956:175936. doi: 10.1016/j.ejphar.2023.175936. Epub 2023 Aug 2.
Upacicalcet (formerly SK-1403/AJT240) is a novel non-peptide calcimimetic agent that acts as a calcium-sensing receptor (CaSR) agonist for the treatment of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). We compared upacicalcet with other calcimimetics (etelcalcetide or cinacalcet) and examined its in vitro and in vivo characteristics in terms of its human CaSR agonistic activity, its efficacy in normal and CKD rats after a single administration, and its effect on gastric emptying in rats. Upacicalcet activated human CaSR depending on the extracellular calcium (Ca) concentration without exhibiting an agonistic action when the extracellular Ca level was below the physiological level. On the other hand, etelcalcetide had an agonistic activity even in the absence of physiological levels of extracellular Ca. The intravenous administration of upacicalcet to normal and double-nephrectomized rats dose-dependently (0.03-3mg/kg and 0.3-30mg/kg, respectively) decreased the serum intact parathyroid hormone (iPTH) and serum Ca levels; however, the effect of upacicalcet on the reduction in serum Ca disappeared at extracellular Ca levels below the physiologically range, even when administered at a dose higher (100-fold) than the effective dose. Furthermore, upacicalcet did not affect gastric emptying in normal rats when administered up to a dose of 10mg/kg (300-fold higher than the dose affecting serum iPTH levels), while the administration of cinacalcet significantly slowed gastric emptying by approximately 50%. These findings suggest that upacicalcet has potential as an alternative calcimimetic agent with good pharmacological properties and a lower risk of hypocalcemia and gastrointestinal complications.
乌帕立钙（前身为 SK-1403/AJT240）是一种新型的非肽类拟钙剂，作为钙敏感受体（CaSR）激动剂，用于治疗慢性肾脏病（CKD）中的继发性甲状旁腺功能亢进症（SHPT）。我们比较了乌帕立钙与其他拟钙剂（依特卡肽或西那卡塞），并从人 CaSR 激动活性、单次给药后在正常和 CKD 大鼠中的疗效以及对大鼠胃排空的影响等方面，考察了其体外和体内特性。乌帕立钙依赖于细胞外钙（Ca）浓度激活人 CaSR，而当细胞外 Ca 水平低于生理水平时，不会表现出激动作用。另一方面，依特卡肽即使在缺乏生理水平的细胞外 Ca 的情况下也具有激动活性。乌帕立钙静脉注射到正常和双肾切除大鼠中，剂量依赖性地（0.03-3mg/kg 和 0.3-30mg/kg，分别）降低血清全段甲状旁腺激素（iPTH）和血清 Ca 水平；然而，当细胞外 Ca 水平低于生理范围时，乌帕立钙对降低血清 Ca 的作用消失，即使以比有效剂量高 100 倍的剂量给药也是如此。此外，当给予高达 10mg/kg（比影响血清 iPTH 水平的剂量高 300 倍）的乌帕立钙时，它不会影响正常大鼠的胃排空，而给予西那卡塞则会使胃排空显著减慢约 50%。这些发现表明，乌帕立钙具有作为一种替代拟钙剂的潜力，具有良好的药理学特性和较低的低钙血症和胃肠道并发症风险。
