Brown Alex J, Finch Jane, Takahashi Fumiaki, Slatopolsky Eduardo
Renal Division, Washington University School of Medicine, St. Louis, Missouri.
J Am Soc Nephrol. 2000 Nov;11(11):2088-2094. doi: 10.1681/ASN.V11112088.
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 [(3)H]19-norD(2) or[(3)H]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.
19-去甲-1,25(OH)₂D₂（19-去甲D₂）已被证明能有效抑制甲状旁腺激素，但与1,25(OH)₂D₃相比，其血钙活性较低。本研究调查了解释对19-去甲D₂血钙反应降低的潜在机制。单次注射后[(³H]19-去甲D₂或[(³H]1,25(OH)₂D₃的组织定位没有差异。在维生素D缺乏的大鼠中，单次注射60或600 pmol的19-去甲D₂或1,25(OH)₂D₃后24小时测量的肠道钙吸收和骨动员，这两种化合物使其增强到相似程度。然而，当正常大鼠每隔一天用240 pmol的19-去甲D₂或1,25(OH)₂D₃治疗时，首次注射后24小时血清钙的升高是相同的，但此后出现差异，到第5天时，19-去甲D₂治疗的大鼠血清钙显著降低。在维生素D缺乏的大鼠中，每天注射600 pmol的19-去甲D₂或1,25(OH)₂D₃七次后，重新评估肠道钙吸收和骨钙动员，19-去甲D₂治疗的大鼠这两个参数均显著较低。每天注射600 pmol的19-去甲D₂或1,25(OH)₂D₃七次后的药代动力学分析显示，它们在肠道和骨骼中的定位相似。此外，用19-去甲D₂或1,25(OH)₂D₃治疗1周后，肠道维生素D受体水平没有差异。总之，19-去甲D₂的低血钙活性似乎是由于肠道和骨骼对该类似物的慢性治疗产生了获得性的受体后抗性。
