Calcifediol

Vitamin D receptor (VDR) activation is associated with cardiovascular and survival benefits in chronic kidney disease patients. Calcifediol, also known as calcidiol, is a prehormone that is produced in the liver by hydroxylation of vitamin D3.

In vitro: Calcifediol induced CYP24A1 expression with EC50 at 70 nM. Calcifediol stimulated the expression of thrombomodulin with EC50 at 10-100 nM. Confocal microscopy revealed that calcifediol at 0.1 - 10 μM induced VDR translocation into the nucleus dose-dependently; the VDR localization pattern was similar in cells treated with calcitriol [1].

In vivo: Spontaneously hypertensive rats and normotensive Wistar-Kyoto (WKY) rats were injected with either 50 ng/d calcifediol or vehicle alone for 3 days. Decreased calbindin-D9K and cellular Ca2+ flux were observed in control SHR. Calcifediol increased total cell and brush border calbindin-D9K. In contrast, Ca2+ flux, which increased in vit-D animals, remained lower in SHR for plasma calcitriol levels similar to those in WKY rats [2].

Clinical trial: Calcifediol given daily, weekly, or as a single bolus is about 2-3 times more potent in increasing plasma 25(OH)D3 concentrations than vitamin D3. Plasma 25(OH)D3 concentrations of 30 ng/mL were reached more rapidly and reliably with calcifediol [3].

Reference:
[1] Wu-Wong JR, Chen YW, Nakane M, Wolf M.  Differential effects of vitamin d receptor agonists on gene expression in neonatal rat cardiomyocytes. Cardiovasc Drugs Ther. 2011 Jun;25(3):215-22.
[2] Roullet CM, Roullet JB, Martin AS, McCarron DA.  In vivo effect of calcitriol on calcium transport and calcium binding proteins in the spontaneously hypertensive rat. Hypertension. 1994 Aug;24(2):176-82.
[3] Jetter A, Egli A, Dawson-Hughes B, Staehelin HB, Stoecklin E, Goessl R, Henschkowski J, Bischoff-Ferrari HA.  Pharmacokinetics of oral vitamin D(3) and calcifediol. Bone. 2014 Feb;59:14-9.

Calcifediol-loaded liposomes for local treatment of pulmonary bacterial infections.[Pubmed:27888144]

Eur J Pharm Biopharm. 2017 Sep;118:62-67.

The influence of vitamin D3 and its metabolites Calcifediol (25(OH)D) and calcitriol on immune regulation and inflammation is well described, and raises the question of potential benefit against bacterial infections. In the current study, 25(OH)D was encapsulated in liposomes to enable aerosolisation, and tested for the ability to prevent pulmonary infection by Pseudomonas aeruginosa. Prepared 25(OH)D-loaded liposomes were nanosized and monodisperse, with a negative surface charge and a 25(OH)D entrapment efficiency of approximately 23%. Jet nebulisation of liposomes was seen to yield an aerosol suitable for tracheo-bronchial deposition. Interestingly, 25(OH)D in either liposomes or ethanolic solution had no effect on the release of the proinflammatory cytokine KC from Pseudomonas-infected murine epithelial cells (LA-4); treatment of infected, human bronchial 16-HBE cells with 25(OH)D liposomes however resulted in a significant reduction in bacterial survival. Together with the importance of selecting an application-appropriate in vitro model, the current study illustrates the feasibility and practicality of employing liposomes as a means to achieve 25(OH)D lung deposition. 25(OH)D-loaded liposomes further demonstrated promising effects regarding prevention of Pseudomonas infection in human bronchial epithelial cells.

Effects of Cholecalciferol vs Calcifediol on Total and Free 25-Hydroxyvitamin D and Parathyroid Hormone.[Pubmed:28187226]

J Clin Endocrinol Metab. 2017 Apr 1;102(4):1133-1140.

Context: Vitamin D deficiency disproportionately affects nonwhite individuals. Controversy persists over how to best restore low 25D levels, and how to best define vitamin D status [total (protein bound plus free) vs free 25D]. Objective: To assess the effects of vitamin D3 (cholecalciferol, or D3) vs 25-hydroxyvitamin D3 (Calcifediol, or 25D3) on total and free 25D in a multiethnic cohort of adults, and whether change in parathyroid hormone (PTH) is more strongly associated with total vs free 25D. Design: Sixteen-week randomized controlled trial. Biochemistries at 0, 4, 8, and 16 weeks. Setting: Academic medical center. Participants: Thirty-five adults >/=18 years of age with 25D levels <20 ng/mL. Intervention: Sixty micrograms (2400 IU)/d of D3 or 20 mug/d of 25D3. Main Outcome Measures: Total and free 25D, and PTH. Results: Baseline total (16.2 +/- 3.7 vs 17.0 +/- 2.5 ng/mL; P = 0.4) and free (4.2 +/- 0.8 vs 4.7 +/- 1.0 pg/mL; P = 0.2) 25D were similar between D3 and 25D3 groups, respectively; 25D3 increased total (+25.5 vs +13.8 ng/mL; P = 0.001) and free (+6.6 vs +3.5 pg/mL; P = 0.03) 25D more than D3. By 4 weeks, 87.5% of 25D3 participants had total 25D levels >/=30 ng/mL, compared with 23.1% of D3 participants (P = 0.001). Change in PTH was associated with both total (P = 0.01) and free 25D (P = 0.04). Conclusions: 25D3 increased total and free 25D levels more rapidly than D3, regardless of race/ethnicity. Free and total 25D were similarly associated with change in PTH.

Effectiveness of Calcifediol in Improving Muscle Function in Post-Menopausal Women: A Prospective Cohort Study.[Pubmed:28205055]

Adv Ther. 2017 Mar;34(3):744-752.

INTRODUCTION: The role of vitamin D supplementation on muscle function and physical performance is still debated. Calcifediol is an available treatment for hypovitaminosis D, particularly for extra-skeletal effects. Aim of this prospective cohort study was to evaluate the effectiveness of Calcifediol on serum levels of 25(OH)D3, appendicular muscle strength, physical performance, and prevention of falls in post-menopausal women. METHODS: We recruited post-menopausal women aged >/=50 years, referring to an outpatient service for the management of osteoporosis over a 18-month period. We included women with a diagnosis of osteoporosis and/or vitamin D deficiency [serum levels of 25(OH)D3 <30 ng/ml]. All the participants received Calcifediol (20 mug, 4 oral drops/day) for a 6-month period. We evaluated at the baseline and after 6 months the following outcomes: serum levels of 25(OH)D3, appendicular muscle strength, using the Isometric Hand Grip Strength Test and the Knee Isometric Extension Strength Test, physical performance, using the Short Physical Performance Battery (SPPB) and the 4-m gait speed (4MGS), and the risk of falls (percentage of fallers and recurrent fallers and mean number of falls). A sub-analysis was performed in patients with vitamin D deficiency. RESULTS: We enrolled 113 post-menopausal women, mean aged 68.01 +/- 9.13 years. After 6 months of treatment, there was a significant increase in serum levels of 25(OH)D3 (p < 0.001), appendicular muscle strength (p < 0.001), and physical performance (p = 0.002 at SPPB and p = 0.010 at 4MGS, respectively). At 6 months, the percentage of fallers was lower, although not significantly (p = 0.078), whereas there was a significant reduction both in percentage of recurrent fallers and in the mean number of falls (p < 0.001 and p = 0.020, respectively). CONCLUSION: Calcifediol was significantly effective in improving serum levels of 25(OH)D3 and muscle function and in reducing the percentage of recurrent fallers and the mean number of falls in a cohort of post-menopausal women.

Blood 25-hydroxyvitamin D3 concentrations and incident sporadic colorectal adenoma risk: a pooled case-control study.[Pubmed:20650953]

Am J Epidemiol. 2010 Sep 1;172(5):489-500.

The authors examined the association between circulating 25-hydroxyvitamin D(3) (25(OH)D(3)), the best indicator of total vitamin D exposure, and incident, sporadic colorectal adenoma risk in a pooled analysis of primary data from 3 colonoscopy-based case-control studies conducted in Minnesota, North Carolina, and South Carolina between 1991 and 2002. The pooled study included 616 colorectal adenoma cases and 770 polyp-free controls. Multivariable logistic regression was used to estimate the association between circulating 25(OH)D(3) and colorectal adenoma risk. Stratified analyses and the likelihood ratio test were used to examine effect modification by various risk factors. In the pooled analysis, higher circulating 25(OH)D(3) concentrations were statistically significantly associated with decreased colorectal adenoma risk (highest vs. lowest quartile odds ratio = 0.59, 95% confidence interval: 0.41, 0.84). The observed inverse association was stronger among participants who used nonsteroidal antiinflammatory drugs regularly (highest vs. lowest quartile odds ratio = 0.33, 95% confidence interval: 0.19, 0.56). Inverse associations between 25(OH)D(3) and colorectal adenoma did not differ substantially by other risk factors or by adenoma characteristics. These findings support the hypothesis that greater vitamin D exposure may reduce the risk of colorectal adenoma and suggest that it may do so more strongly in combination with antiinflammatory agents.

25-Hydroxyvitamin D(3) suppresses PTH synthesis and secretion by bovine parathyroid cells.[Pubmed:16807549]

Kidney Int. 2006 Aug;70(4):654-9.

Active vitamin D compounds repress parathyroid hormone (PTH) gene transcription and block chief cell hyperplasia, making them integral tools in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease. Recently, human parathyroid glands have been shown to express 25-hydroxyvitamin D 1alpha-hydroxylase (1alphaOHase), but documentation of the 1alphaOHase activity in parathyroid cells and its potential role in activating 25-hydroxyvitamin D(3) (25(OH)D(3)) to 1,25-dihydroxyvitamin D(3) (1,25(OH)2D3) have not been reported. The relative potencies of 25(OH)D(3) and 1,25(OH)(2)D(3) in reducing PTH secretion and mRNA were determined in primary cultures of bovine parathyroid cells (bPTC). The effects of blocking 1alphaOHase activity on suppression of PTH mRNA and induction of 24-hydroxylase mRNA were examined. Vitamin D receptor (VDR) affinities were estimated by intact cell competitive binding assay. Metabolism of 25(OH)D(3) by bPTC was assessed using a radioimmunoassay that measures all 1-hydroxylated metabolites of vitamin D. 25(OH)D(3) suppressed PTH secretion and mRNA (ED(50)=2 nM), but was several hundred times less potent than 1,25(OH)(2)D(3). The lower potency of 25(OH)D(3) correlated with its lower VDR affinity. bPTCs converted 25(OH)D(3) to 1-hydroxylated metabolites, but the rate of conversion was low. Inhibition of 1alphaOHase with the cytochrome P450 inhibitor clotrimazole did not block 25(OH)D(3)-mediated suppression of PTH. Clotrimazole enhanced 24-hydroxylase mRNA induction, presumably by inhibiting catabolism of 25(OH)D(3). In conclusion, 25(OH)D(3) suppresses PTH synthesis by parathyroid cells, possibly by direct activation of the VDR.

Megalin-mediated endocytosis of vitamin D binding protein correlates with 25-hydroxycholecalciferol actions in human mammary cells.[Pubmed:17056796]

J Nutr. 2006 Nov;136(11):2754-9.

The major circulating form of vitamin D is 25-hydroxycholecalciferol [25(OH)D3], which is delivered to target tissues in complex with the serum vitamin D binding protein (DBP). We recently observed that mammary cells can metabolize 25(OH)D3 to 1,25-dihydroxycholecalciferol [1,25(OH)(2)D3], the vitamin D receptor (VDR) ligand, and the objective of our study was to elucidate the mechanisms by which the 25(OH)D3-DBP complex is internalized by mammary cells prior to metabolism. Using fluorescent microscopy and temperature-shift techniques, we found that T-47D breast cancer cells rapidly internalize DBP via endocytosis, which is blunted by receptor-associated protein, a specific inhibitor of megalin-mediated endocytosis. Endocytosis of DBP was associated with activation of VDR by 25(OH)D3 but not 1,25(OH)(2)D3 (as measured by induction of the VDR target gene, CYP24). We also found that megalin and its endocytic partner, cubilin, are coexpressed in normal murine mammary tissue, in nontransformed human mammary epithelial cell lines, and in some established human breast cancer cell lines. To our knowledge, our studies are the first to demonstrate that mammary-derived cells express megalin and cubilin, which contribute to the endocytic uptake of 25(OH)D3-DBP and activation of the VDR pathway.

Calcifediol is a major circulating metabolite of vitamin D3, acting as a competitive inhibitor with an apparent Ki of 3.9 μM, suppresses PTH secretion and mRNA (ED50=2 nM).

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