title: Eldecalcitol replaces endogenous calcitriol but does not fully compensate for its action in vivo.
abstract: Calcitriol (1α,25-dihydroxyvitamin D3, 1α,25(OH)2D3) is an essential hormone that works in cooperation with parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) to regulate calcium and phosphorus homeostasis. Previous in vivo studies in rats have shown that eldecalcitol, a vitamin D analog, is more active than calcitriol in stimulating calcium and phosphorus absorption in the intestine and in increasing serum FGF-23, but is not as active in suppressing blood PTH. However, those results are problematic because administration of exogenous eldecalcitol or calcitriol affects the synthesis and degradation of endogenous calcitriol, and competes for binding to vitamin D receptor (VDR) in target tissues. Therefore, we tried to evaluate the 'true biological activity in vivo' of each compound by comparing their biological activities with respect to their blood concentrations. In VDR gene knockout mice, calcitriol and eldecalcitol did not affect either serum or urinary calcium levels, and also did not induce the expression of target genes. These results indicate that the actions of eldecalcitol are mediated by VDR. In normal rats, concentrations of both calcitriol and eldecalcitol in the blood increased dose-dependently and had a linear correlation with administered dosage. The concentration of calcitriol in the blood was reduced by eldecalcitol treatment, falling to below the limit of detection at 0.1μg/kg eldecalcitol. Based on the concentration of each compound in the blood, eldecalcitol had approximately 1/4 to 1/7 the activity of calcitriol to increase serum calcium, FGF-23, and urinary calcium excretion, and to suppress blood PTH. Eldecalcitol dose-dependently increased urinary phosphorus excretion and reduced serum phosphorus. However, calcitriol did not change serum phosphorus. In accordance with serum chemistry and hormones, a concentration of eldecalcitol in the blood of 3-8 times that of calcitriol was required to stimulate target gene expressions in the kidneys (VDR, TRPV5, and calbindin-D28k) and bone (VDR, FGF-23, and RANKL). On the other hand, the blood concentrations of eldecalcitol needed to stimulate target genes in the intestine (TRPV6, calbindin-D9k, and VDR) were comparable to those of calcitriol. These results indicate that oral administration of eldecalcitol stimulates target gene expression in the intestine similarly to calcitriol, but to a much lesser extent than calcitriol in the kidneys and bones. The major finding of the present study is that eldecalcitol suppresses endogenous calcitriol and replaces it. However, it may not fully compensate for the action of calcitriol in vivo. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.
authors.affiliation: Medical Affairs Division, Chugai Pharmaceutical Co., Ltd., Tokyo 103-8324, Japan. Electronic address: saitohts@chugai-pharm.co.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Saito
authors.affiliation: Medical Affairs Division, Chugai Pharmaceutical Co., Ltd., Tokyo 103-8324, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Harada
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002117:Calcitriol / Q000494:pharmacology*; D000089703:Fibroblast Growth Factor-23; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051379:Mice; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D050071:Bone Density Conservation Agents; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D018167:Receptors, Calcitriol; D014807:Vitamin D; D000089703:Fibroblast Growth Factor-23; D002117:Calcitriol; C547512:eldecalcitol
keywords: Calcium; Eldecalcitol; Phosphorus; VDR