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Calcemic Activity of 19-Nor-1,25(OH)2D2 Decreases with Duration of Treatment

2000; American Society of Nephrology; Volume: 11; Issue: 11 Linguagem: Inglês

10.1681/asn.v11112088

1533-3450

Alex J. Brown, Jane Finch, Fumiaki Takahashi, Eduardo Slatopolsky,

Thyroid Disorders and Treatments

Abstract. 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.