The Vitamin D Analog ED-71 Is a Potent Regulator of Intestinal Phosphate Absorption and NaPi-IIb

The vitamin D analog ED-71 [1α,25-dihydroxy-2β-(3-hydroxypropyloxy)vitamin D3] has been approved for treatment of osteoporosis in Japan, but its effects on mineral metabolism have not been fully explored. We investigated the actions of ED-71 on phosphate (Pi) absorption and induction of the intestin...

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Published in:Endocrinology (Philadelphia) 2012-11, Vol.153 (11), p.5150-5156
Main Authors: Brown, Alex J, Zhang, Fanjie, Ritter, Cynthia S
Format: Article
Language:English
Subjects:
Absorption - drug effects
Animals
Biological and medical sciences
Calcitriol - analogs & derivatives
Calcitriol - pharmacology
Fundamental and applied biological sciences. Psychology
Intestines - drug effects
Intestines - metabolism
Male
Mice
Mice, Knockout
Phosphates - metabolism
Rats
Rats, Sprague-Dawley
Receptors, Calcitriol - genetics
Receptors, Calcitriol - metabolism
Sodium-Phosphate Cotransporter Proteins, Type IIb - genetics
Sodium-Phosphate Cotransporter Proteins, Type IIb - metabolism
Vertebrates: endocrinology
Vitamin D - analogs & derivatives
Vitamin D Deficiency - metabolism
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Summary:The vitamin D analog ED-71 [1α,25-dihydroxy-2β-(3-hydroxypropyloxy)vitamin D3] has been approved for treatment of osteoporosis in Japan, but its effects on mineral metabolism have not been fully explored. We investigated the actions of ED-71 on phosphate (Pi) absorption and induction of the intestinal sodium/phosphate cotransporters. Oral treatment of vitamin D-deficient rats with ED-71 (20 pmol every other day for 8 d) produced a maximal 8-fold increase in duodenal Pi absorption, measured by the in situ loop method, whereas 1,25-dihyroxyvitamin D3 [1,25(OH)2D3], at doses up to 150 pmol, had no effect. This action of ED-71 was attributable to a dramatic 24-fold induction of sodium-dependent Pi transporter type IIb (NaPi-IIb) mRNA in the duodenum; Pit-1 and Pit-2 mRNA levels were not increased. In vitamin D-replete rats, ED-71 treatment (50 pmol) at 72 and 24 h before death increased NaPi-IIb mRNA in the duodenum and jejunum, but not the ileum, whereas 1,25(OH)2D3 at 1000 pmol was ineffective in all segments. Single oral doses of ED-71 increased mouse intestinal NaPi-IIb mRNA and protein between 6 and 24 h. Surprisingly, rat lung NaPi-IIb was not increased by ED-71, despite its coexpression with the vitamin D receptor in alveolar type II cells. However, ED-71 did not induce intestinal NaPi-IIb in vitamin D receptor-ablated mice. The greater potency of ED-71 than 1,25(OH)2D3 on NaPi-IIb appears to be due to much higher and more prolonged levels of ED-71 in the circulation. In summary, ED-71, due to its disparate pharmacokinetics, is a much more potent inducer of intestinal Pi absorption and NaPi-IIb than 1,25(OH)2D3, suggesting a role for this analog in the treatment of Pi-wasting disorders.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2012-1587