Kondo Satoshi, Takano Toshiyuki, Ono Yoshiyuki, Saito Hitoshi, Matsumoto Toshio
Chugai Pharmaceutical Co., Ltd., Tokyo 103-8324, Japan.
Fujii Memorial Institute of Medical Research, University of Tokushima, Tokushima 770-8503, Japan.
J Steroid Biochem Mol Biol. 2015 Apr;148:232-8. doi: 10.1016/j.jsbmb.2015.01.016. Epub 2015 Jan 24.
Eldecalcitol shows higher binding affinity for vitamin D-binding protein (DBP), tighter binding to vitamin D receptor (VDR), and resistance to metabolic degradation via 24-hydroxylation. In silico analysis of the mode of binding demonstrated that the 3-hydroxypropyloxy (3-HP) group of eldecalcitol offers additional hydrogen bond and CH-π interaction for the binding to DBP and VDR. However, the 3-HP group interferes with the binding of eldecalcitol to CYP24A1, causing poor metabolic clearance of eldecalcitol by this enzyme. These characteristics may contribute to the stronger effect of eldecalcitol than calcitriol. The present post-hoc analysis also demonstrate that the incidence of hypercalcemia and hypercalciuria is slightly higher in eldecalcitol than in alfacalcidol group especially in patients with CKD stage 3B, that both serum and urinary calcium return to the baseline levels shortly after cessation of the treatment in both treatment groups, that the incidence of urolithiasis is higher in patients with higher eGFR and is similar between alfacalcidol and eldecalcitol groups, and that eGFR is transiently reduced by both alfacalcidol and eldecalcitol treatment especially among patients with higher eGFR but recovers after the end of both treatment. Eldecalcitol can be used for the treatment of osteoporosis without Ca supplementation to reduce the incidence of hypercalcemia and hypercalciuria, and enough hydration is recommended in order to avoid hypercalcemia, urolithiasis and deterioration of renal function.
eldecalcitol对维生素D结合蛋白（DBP）表现出更高的结合亲和力，与维生素D受体（VDR）的结合更紧密，并且对通过24-羟化的代谢降解具有抗性。对结合模式的计算机模拟分析表明， eldecalcitol的3-羟丙氧基（3-HP）基团为与DBP和VDR的结合提供了额外的氢键和CH-π相互作用。然而，3-HP基团干扰了 eldecalcitol与CYP24A1的结合，导致该酶对 eldecalcitol的代谢清除率较低。这些特性可能导致 eldecalcitol比骨化三醇具有更强的作用。本事后分析还表明， eldecalcitol组高钙血症和高钙尿症的发生率略高于阿法骨化醇组，尤其是在CKD 3B期患者中；两个治疗组在治疗停止后不久血清和尿钙均恢复到基线水平；eGFR较高的患者尿路结石的发生率较高，阿法骨化醇组和 eldecalcitol组相似；阿法骨化醇和 eldecalcitol治疗均会使eGFR暂时降低，尤其是在eGFR较高的患者中，但在两种治疗结束后会恢复。 eldecalcitol可用于治疗骨质疏松症，无需补充钙剂以降低高钙血症和高钙尿症的发生率，建议充分补水以避免高钙血症、尿路结石和肾功能恶化。
