Twiss I M, Pas O, Ramp-Koopmanschap W, Den Hartigh J, Vermeij P
Leiden University Medical Center, Department of Clinical Pharmacy, Leiden, The Netherlands.
J Bone Miner Res. 1999 May;14(5):784-91. doi: 10.1359/jbmr.1999.14.5.784.
Nitrogen-containing bisphosphonates (N-PCP) are bisphosphonates with an increased antiresorptive potency. Aminobisphosphonates, N-PCPs with an amino group, can cause nonspecific gastrointestinal complaints. It is not known whether these side effects are specific for these bisphosphonates or for the whole class of N-PCPs. In this study, we investigated the effects of two aminobisphosphonates (pamidronate and alendronate) and a structurally similar N-PCP (olpadronate) and their three respective calcium complexes on the viability and the intracellular calcium concentration ([Ca2+]i) of cultured Caco-2 cells a model for intestinal epithelium. These cells were also examined for apoptosis or necrosis. In the presence of calcium, pamidronate and alendronate were toxic to the cells, with pamidronate being more toxic than alendronate. Olpadronate induced toxicity only at concentrations more than ten times higher than the toxic concentrations of pamidronate. In the absence of calcium definite signs of toxicity were observed only with pamidronate at clinically relevant concentrations. The complexes of pamidronate and alendronate with calcium were considerably less soluble than the olpadronate calcium complex. There were no signs of apoptosis. [Ca2+]i was transiently raised after treatment with the N-PCPs. Doses at which responses were seen were, respectively, 0.02 mM (pamidronate), 0.3 mM (alendronate), and 2 mM (olpadronate). The peak of response was slightly greater after pamidronate treatment than after alendronate or olpadronate, respectively. In conclusion pamidronate, either as an ion or as a calcium complex, is the most toxic of the bisphosphonates tested for Caco-2 cells. Alendronate was less toxic while olpadronate was the least toxic in presence of calcium. The solubility of the bisphosphonate complexes with calcium may account for these differences in toxicity.
含氮双膦酸盐（N - PCP）是一类抗吸收效力增强的双膦酸盐。氨基双膦酸盐是带有氨基的N - PCP，可引起非特异性胃肠道不适。目前尚不清楚这些副作用是这些双膦酸盐所特有的，还是整个N - PCP类药物共有的。在本研究中，我们研究了两种氨基双膦酸盐（帕米膦酸盐和阿仑膦酸盐）以及一种结构相似的N - PCP（奥帕膦酸盐）及其三种相应的钙络合物对培养的Caco - 2细胞（一种肠上皮细胞模型）的活力和细胞内钙浓度（[Ca2 + ]i）的影响。还对这些细胞进行了凋亡或坏死检测。在有钙存在的情况下，帕米膦酸盐和阿仑膦酸盐对细胞有毒性，其中帕米膦酸盐的毒性比阿仑膦酸盐更强。奥帕膦酸盐仅在浓度高于帕米膦酸盐毒性浓度十倍以上时才诱导毒性。在无钙情况下，仅在临床相关浓度的帕米膦酸盐中观察到明确的毒性迹象。帕米膦酸盐和阿仑膦酸盐与钙的络合物的溶解度远低于奥帕膦酸盐钙络合物。未观察到凋亡迹象。用N - PCP处理后，[Ca2 + ]i短暂升高。出现反应的剂量分别为0.02 mM（帕米膦酸盐）、0.3 mM（阿仑膦酸盐）和2 mM（奥帕膦酸盐）。帕米膦酸盐处理后的反应峰值分别略高于阿仑膦酸盐或奥帕膦酸盐处理后的反应峰值。总之，对于Caco - 2细胞而言，帕米膦酸盐无论是作为离子还是作为钙络合物，都是所测试的双膦酸盐中毒性最强的。在有钙存在的情况下，阿仑膦酸盐毒性较小，而奥帕膦酸盐毒性最小。双膦酸盐与钙的络合物的溶解度可能解释了这些毒性差异。
