Vitamin D receptor

In mice undergoing nephrectomy, doxercalciferol (100 or 300 pg/g b.w.) restores serum calcium and parathyroid hormone (PTH) levels to normal. In mice undergoing nephrectomy, doxercalciferol (300 pg/g b.w.) significantly lowers osteitis fibrosa. In rats given a high-salt (HS) diet, doxercalciferol significantly reduces cardiac hypertrophy and enhances cardiac function. In rats fed a high salt (HS) diet, doxercalciferol treatment results in a significant decrease in tissue atrial natriuretic factor (ANF) mRNA level and plasma brain natriuretic peptide (BNP) level. Additionally, doxercalciferol dramatically lowers protein kinase C-α (PKCα) levels, indicating a possible link between vitamin D deficiency and PKC-mediated cardiac hypertrophy. In diet-induced obese (DIO) mice, doxercalciferol reduces proteinuria, podocyte damage, mesangial growth, and extracellular matrix protein accumulation. In DIO mice, doxercalciferol also reduces profibrotic growth factors, proinflammatory cytokines, oxidative stress, and macrophage infiltration. Moreover, doxercalciferol inhibits the DIO mice's renin-angiotensin-aldosterone system activation, which includes the angiotensin II type 1 receptor and the mineralocorticoid receptor. In mice, the combination of doxercalciferol and losartan most effectively prevents albuminuria, restores the structure of the glomerular filtration barrier, and significantly lowers glomerulosclerosis in a dose-dependent manner. Mice's diabetic kidneys show virtually no morphological or molecular changes when doxercalciferol and losartan are combined.

In 5/6 nephrectomized (NX) rats, Doxercalciferol (0.083, 0.167, or 0.333 μg/kg, i.p.) raises serum phosphorus at Week 6. In addition, doxercalciferol (0.167 and 0.333 μg/kg) enhances increased pulse wave velocity (PWV) in 5/6 nephrectomized (NX) rats at Week 6 and raises serum calcium and Ca × P at Weeks 2 and 6. Doxercalciferol decreases serum PTH to the SHAM level and prevents PTH from rising at 0.083 μg/kg[1]. In NON mice fed a high-fat diet, doxercalciferol (125 ng/kg, i.p., three times a week) increases the expression of VDR mRNA level and renal expression of TRPV5. In mice given an HF diet, doxercalciferol also reduces proteinuria, stops podocyte loss, and reduces the buildup of extracellular matrix proteins. In mice fed an HF diet, doxercalciferol blocks increased expression of the renin-angiotensin-aldosterone system and inhibits the expression of profibrotic growth factors (TGF-β, PAI-1, and connective tissue growth factor (CTGF)). In addition, Doxercalciferol inhibits the infiltration of macrophages, lowers NF-κb activity, stops the expression of proinflammatory cytokines, and stops the accumulation of renal lipids in mice given a high-fat diet[2]. When administered intraperitoneally (i.p.) three times a week to streptozotocin-induced diabetic mice, doxercalciferol (30 ng/kg) significantly attenuates podocyte loss and apoptosis and decreases glomerular fibrosis[3].

Rats: One week following nephrectomy, male Sprague-Dawley 5/6 nephrectomized (NX) rats (∼200 mg) are used. A typical surgical ablation procedure consisting of two steps is used to perform the nephrectomy. Rats are kept on a high-phosphorus diet (0.9% phosphorus and 0.6% calcium) for the duration of the study starting two weeks after nephrectomy in order to cause secondary hyperparathyroidism. Day 0: Vehicle (5% EtOH/95% propylene glycol; 0.4 mL/kg; i.p.) or VDRA (paricalcitol or Doxercalciferol; 0.083, 0.167, or 0.333 μg/kg; intraperitoneally) is given three times a week for 41 days (n = 6–10 per group) to SHAM and 5/6 NX rats (n = 7–10 per group). These dosages were selected because, in this CKD model, after two or six weeks of treatment, lower doses (0.021 and 0.042 μg/kg; i.p.) of either compound do not suppress PTH. Days 0 through 41 are when blood is drawn (24 hours after the dose). Animals are given ketamine (50 mg/kg) anesthesia on Days 0, 13, and 41 (24 h post-dose), and blood is drawn from the tail vein for measurements of PTH and serum blood chemistry[1].

Metabolism / Metabolites
Doxercalciferol is absorbed from the gastrointestinal tract and activated by CYP 27 in the liver to form 1α,25-(OH)2D2 (major metabolite) and 1α,24-dihydroxyvitamin D2 (minor metabolite). Activation of doxercalciferol does not require the involvement of the kidneys.

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Biological Half-Life
32 to 37 hours.

[1]. Differential effects of vitamin D receptor activators on aortic calcification and pulse wave velocity in uraemic rats. Nephrol Dial Transplant. 2008 Dec;23(12):3824-30.

[2]. Vitamin D receptor agonist doxercalciferol modulates dietary fat-induced renal disease and renal lipid metabolism. Am J Physiol Renal Physiol. 2011 Mar;300(3):F801-10.

[3]. Vitamin D receptor signaling in podocytes protects against diabetic nephropathy. J Am Soc Nephrol. 2012 Dec;23(12):1977-86.

Doxercalciferol is a hydroxy seco-steroid and synthetic vitamin D2 analogue that undergoes metabolic activation in vivo to form 1alpha,25-dihydroxyvitamin D2 (1alpha,25-(OH)2D2), a naturally occurring, biologically active form of vitamin D2. It is used to treat secondary hyperparathyroidism, a condition in which the body produces excess parathyroid hormone (PTH; a natural substance needed to control the amount of calcium in the blood) in certain people with chronic kidney disease. It has a role as a provitamin, a bone density conservation agent and a prohormone. It is a vitamin D and a hydroxy seco-steroid.
Doxercalciferol is a synthetic vitamin D2 analog that undergoes metabolic activation in vivo to form 1α,25-dihydroxyvitamin D2 (1α,25-(OH)2D2), a naturally occurring, biologically active form of vitamin D2. Doxercalciferol is indicated for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, as well as for the treatment of secondary hyperparathyroidism in patients with Stage 3 or Stage 4 chronic kidney disease. Doxercalciferol is marketed under the brand name Hectoral by Genzyme Corporation, and is manufactured by Catalent Pharma Solutions, Inc.
Doxercalciferol is a Vitamin D2 Analog.
Doxercalciferol is a synthetic analog of vitamin D with potential antineoplastic activity. In the liver, doxercalciferol is converted to its biologically active vitamin D metabolites, which control the intestinal absorption of dietary calcium, the tubular reabsorption of calcium by the kidney and, in conjunction with parathyroid hormone (PTH), the mobilization of calcium from the skeleton. Through interaction with specific receptor proteins in target tissues, these vitamin D metabolites act directly on osteoblasts to stimulate skeletal growth, and on the parathyroid glands to suppress PTH synthesis and secretion. This agent has also been shown to inhibit the growth of retinoblastomas, and may exhibit some antiproliferative activity against prostate cancer cells.

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Drug Indication
Doxercalciferol is indicated for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, as well as for the treatment of secondary hyperparathyroidism in patients with Stage 3 or Stage 4 chronic kidney disease.
FDA Label

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Mechanism of Action
Calcitriol (1α,25-(OH)2D3) and 1α,25-(OH)2D2 regulate blood calcium at levels required for essential body functions. Specifically, the biologically active vitamin D metabolites control the intestinal absorption of dietary calcium, the tubular reabsorption of calcium by the kidney and, in conjunction with parathyroid hormone (PTH), the mobilization of calcium from the skeleton. They act directly on bone cells (osteoblasts) to stimulate skeletal growth, and on the parathyroid glands to suppress PTH (parathyroid hormone) synthesis and secretion. These functions are mediated by the interaction of these biologically active metabolites with specific receptor proteins in the various target tissues. In patients with chronic kidney disease (CKD), deficient production of biologically active vitamin D metabolites (due to lack of or insufficient 25-hydroxyvitamin D-1-alpha-hydroxylase activity) leads to secondary hyperparathyroidism, which contributes to the development of metabolic bone disease.

C28H44O2

412.65

412.334

C, 81.50; H, 10.75; O, 7.75

54573-75-0

trans-Doxercalciferol;74007-20-8;Impurity of Doxercalciferol;127516-23-8

5281107

White to yellow/brown solid powder

1.0±0.1 g/cm3

538.7±50.0 °C at 760 mmHg

138-140ºC

224.0±24.7 °C

0.0±3.3 mmHg at 25°C

1.541

8.15

2

2

5

30

712

7

C=C1[C@H](C[C@@H](C/C1=C/C=C2[C@]3([C@@](C)([C@H](CC3)[C@@H](/C=C/[C@@H](C(C)C)C)C)CCC/2)[H])O)O

HKXBNHCUPKIYDM-CGMHZMFXSA-N

InChI=1S/C28H44O2/c1-18(2)19(3)9-10-20(4)25-13-14-26-22(8-7-15-28(25,26)6)11-12-23-16-24(29)17-27(30)21(23)5/h9-12,18-20,24-27,29-30H,5,7-8,13-17H2,1-4,6H3/b10-9+,22-11+,23-12-/t19-,20+,24+,25+,26-,27-,28+/m0/s1

(1R,3S,5Z)-5-[(2E)-2-[(1R,3aS,7aR)-1-[(E,2R,5R)-5,6-dimethylhept-3-en-2-yl]-7a-methyl-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). This product is not stable in solution, please use freshly prepared working solution for optimal results.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.06 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.06 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)