title: Metabolism of 1 alpha-hydroxyvitamin D2 to activated dihydroxyvitamin D 2 metabolites decreases endogenous 1 alpha, 25-dihydroxyvitamin D 3 in rats and monkeys.
abstract: The vitamin D analog 1 alpha-hydroxyvitamin D2 (1 alpha-OHD2) is under development for the treatment of secondary hyperparathyroidism and metabolic bone disease. This analog is metabolized in vivo to the natural active dihydroxylated metabolite of vitamin D2, 1 alpha,25-dihydroxyvitamin D2 [1 alpha,25-(OH)2D2]. To study the metabolism of this analog, an assay involving HPLC separation and purification of metabolites followed by RRA with the vitamin D receptor was developed to quantitate the active metabolites of the analog and the endogenous active metabolite of vitamin D3, 1 alpha,25-(OH)2D3, from the same blood sample. This assay was used to determine blood levels of active dihydroxylated vitamin D compounds in rats and monkeys treated with oral 1 alpha-OHD2. As the circulating 1 alpha,25-(OH)2D2 level increased dose dependently in these rats and monkeys, a concomitant decrease in the endogenous 1 alpha,25-(OH)2D3 was observed. In rats orally administered more than 2.5 micrograms 1 alpha-OHD2/kg.day, a second active metabolite of 1 alpha-OHD2, 1 alpha,24-(OH)2D2, was detected in concentrations similar to those of 1 alpha,25-(OH)2D2. These results indicate that the regulatory control of endogenous vitamin D metabolism as well as analog metabolism must be considered when assessing the therapeutic potential of a vitamin D analog.
authors.affiliation: Bone Care International, Inc., Madison, Wisconsin 53713, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Knutson
authors.forename: B W
authors.initials: BW
authors.lastname: Hollis
authors.forename: L W
authors.initials: LW
authors.lastname: LeVan
authors.forename: C
authors.initials: C
authors.lastname: Valliere
authors.forename: K G
authors.initials: KG
authors.lastname: Gould
authors.forename: C W
authors.initials: CW
authors.lastname: Bishop
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000097:blood / Q000378:metabolism*; D002118:Calcium / Q000097:blood / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D004872:Ergocalciferols / Q000097:blood / Q000378:metabolism*; D005260:Female; D008252:Macaca fascicularis; D011869:Radioligand Assay / Q000706:statistics & numerical data; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000378:metabolism; D012680:Sensitivity and Specificity
chemical_list: D004872:Ergocalciferols; D018167:Receptors, Calcitriol; C042533:1 alpha-hydroxyergocalciferol; C003564:1,25-dihydroxyergocalciferol; D002117:Calcitriol; D002118:Calcium