Calcemic activity of 19-Nor-1,25(OH)(2)D(2) decreases with duration of treatment.
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.
Brown
Alex J
AJ
Renal Division, Washington University School of Medicine, St. Louis, Missouri.
Finch
Jane
J
Renal Division, Washington University School of Medicine, St. Louis, Missouri.
Takahashi
Fumiaki
F
Renal Division, Washington University School of Medicine, St. Louis, Missouri.
Slatopolsky
Eduardo
E
Renal Division, Washington University School of Medicine, St. Louis, Missouri.
D000818:Animals; D001862:Bone Resorption / Q000139:chemically induced; D002117:Calcitriol / Q000493:pharmacokinetics / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004872:Ergocalciferols / Q000493:pharmacokinetics; D006934:Hypercalcemia / Q000139:chemically induced*; D007267:Injections; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism; D013997:Time Factors; D014018:Tissue Distribution; D014808:Vitamin D Deficiency / Q000378:metabolism
D004872:Ergocalciferols; D018167:Receptors, Calcitriol; C084656:paricalcitol; D002117:Calcitriol; D002118:Calcium