Azuma Y, Sato H, Oue Y, Okabe K, Ohta T, Tsuchimoto M, Kiyoki M
Teijin Institute for Bio-Medical Research, Tokyo, Japan.
Bone. 1995 Feb;16(2):235-45. doi: 10.1016/8756-3282(94)00035-x.
Alendronate is an aminobisphosphonate that acts as a potent inhibitor of osteoclastic bone resorption. To understand the mechanism of action of alendronate in vivo, in this study we investigated the relationship between distribution of [14C]-alendronate in rat bone and its effects on bone resorption in vitro or in rat hypercalcemic models. A single IV dose of 0.05 approximately 1.25 mg/kg inhibited the increase in plasma calcium level induced by bovine PTH or 1 alpha(OH)D3. The minimal effective dose of pamidronate (1.25 mg/kg) and etidronate (over 31.25 mg/kg) were at least 5 times and 25 times, respectively, higher than the dose of alendronate in the rat hypercalcemic model prepared by 1 alpha(OH)D3. The relative potencies of compounds in the hypercalcemic rat models reflected those of inhibitory effects on bone resorption in vitro. We conducted the ivory-slice assay under two conditions: (a) addition of a given bisphosphonate after adherence of the osteoclasts; and (b) preincubation of the ivory slices with a given bisphosphonate. The inhibitory IC50 values of alendronate under condition (b) were similar to those under condition (a). To evaluate the interaction between osteoclasts and alendronate in bone, we investigated the localization of [14C]-alendronate in the tibia of growing rats (4-day-old rats). Alendronate did not distribute uniformly in the tibia. At 1 day after injection (0.05 mg SC), dense labeling was seen primarily under osteoclasts. We injected 0.05 mg/kg of [14C]-alendronate (single i.v.) into rats [14C]-alendronate was rapidly eliminated from plasma, and mainly distributed to the bone in rats. These data suggest that alendronate which distributed on bone surface mainly contributed to the antihypercalcemic action in vivo.
阿仑膦酸钠是一种氨基双膦酸盐，是破骨细胞性骨吸收的强效抑制剂。为了解阿仑膦酸钠在体内的作用机制，在本研究中，我们研究了[14C] - 阿仑膦酸钠在大鼠骨骼中的分布与其对体外骨吸收或大鼠高钙血症模型的影响之间的关系。单次静脉注射剂量为0.05至约1.25mg / kg可抑制牛甲状旁腺激素或1α（OH）D3诱导的血浆钙水平升高。帕米膦酸钠（1.25mg / kg）和依替膦酸钠（超过31.25mg / kg）的最小有效剂量分别比由1α（OH）D3制备的大鼠高钙血症模型中的阿仑膦酸钠剂量高至少5倍和25倍。高钙血症大鼠模型中化合物的相对效力反映了其对体外骨吸收的抑制作用。我们在两种条件下进行了象牙切片试验：（a）破骨细胞附着后加入给定的双膦酸盐；（b）将象牙切片与给定的双膦酸盐预孵育。条件（b）下阿仑膦酸钠的抑制IC50值与条件（a）下相似。为了评估破骨细胞与阿仑膦酸钠在骨中的相互作用，我们研究了[14C] - 阿仑膦酸钠在生长大鼠（4日龄大鼠）胫骨中的定位。阿仑膦酸钠在胫骨中分布不均匀。注射后1天（皮下注射0.05mg），主要在破骨细胞下方可见密集标记。我们向大鼠静脉注射0.05mg / kg的[14C] - 阿仑膦酸钠（单次静脉注射），[14C] - 阿仑膦酸钠从血浆中迅速消除，主要分布于大鼠骨骼中。这些数据表明，分布在骨表面的阿仑膦酸钠主要促成了体内的抗高钙血症作用。
