Calcemic activity of 19-Nor-1,25(OH)2D2 decreases with duration of treatment
Calcemic activity of 19-Nor-1,25(OH)2D2 decreases with duration of treatment
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DOI：
10.1681/asn.v11112088
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发表时间：
2000-11-01
影响因子：
13.6
通讯作者：
Slatopolsky, E
中科院分区：
文献类型：
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作者：
Brown, AJ;Finch, J;Slatopolsky, E
19-Nor-1,25(OH)(2)D-2 (19-norD(2)) 已被证明可有效抑制甲状旁腺激素，但钙血活性低于 1,25(OH)(2)D-3。本研究调查了解释 19-norD(2) 钙血症反应降低的潜在机制。单次注射后 [H-3]19-norD(2) 或 [H-3]1,25(OH)(2)D-3 的组织定位没有不同。单次注射 60 或 600 pmol 19-norD(2) 或 1,25(OH)(2)D-3 24 小时后，在维生素 D 缺乏的大鼠中测量肠道钙吸收和骨动员，两种化合物增强至相似程度。然而，当正常大鼠每隔一天接受 240 pmol 19-norD(2) 或 1,25(OH)(2)D-3 治疗时，首次注射后 24 小时血清钙增加相同，但此后出现分歧，19-norD(2) 治疗大鼠的血清钙在 5 天时显着降低。每天注射 7 次 600 pmol 19-norD(2) 或 1,25(OH)(2)D-3 后，对维生素 D 缺乏大鼠的肠钙吸收和骨钙动员进行了重新评估，并且在 19-norD(2) 治疗的大鼠中，这两个参数均显着降低。每天注射 7 次 600 pmol 19-norD(2) 或 1,25(OH)(2)D-3 后的药代动力学分析显示，在肠道和骨骼中的定位相似。此外，用19-norD(2)或1,25(OH)(2)D-3治疗1周后，肠道维生素D受体水平没有变化。总之，19-norD(2) 的低钙血活性似乎是由于肠道和骨骼对类似物长期治疗的获得性、受体后抵抗所致。
19-Nor-1,25(OH)(2)D-2 (19-norD(2)) has been shown to suppress parathyroid hormone effectively, but with lower calcemic activity than 1,25(OH)(2)D-3. The present study investigated potential mechanisms to explain the reduced calcemic response to 19-norD(2). Tissue localization of [H-3]19-norD(2) or [H-3]1,25(OH)(2)D-3 after a single injection was not different. Intestinal calcium absorption and bone mobilization, measured in vitamin D-deficient rats 24 h after single injections of 60 or 600 pmol of 19-norD(2) or 1,25(OH)(2)D-3, were enhanced to a similar degree by the two compounds. However, when normal rats were treated every other day with 240 pmol of 19-norD(2) or 1,25(OH)(2)D-3, increases in serum calcium were identical 24 h after the first injection but diverged thereafter with significantly lower serum calcium in the 19-norD(2)-treated rats by 5 d. Intestinal calcium absorption and bone calcium mobilization were reassessed in vitamin D-deficient rats after seven daily injections of 600 pmol of 19-norD(2) or 1,25(OH)(2)D-3, and both parameters were significantly lower in the 19-norD(2)-treated rats. Pharmacokinetic analysis after seven daily injections of 600 pmol of 19-norD(2) or 1,25(OH)(2)D-3 showed similar localization to the intestine and bone. In addition, intestinal vitamin D receptor levels were not different after 1 wk of treatment with 19-norD(2) or 1,25(OH)(2)D-3. In conclusion, the low calcemic activity of 19-norD(2) seems to be due to an acquired, postreceptor resistance of the intestine and bone to chronic treatment with the analog.