Human Endogenous Metabolite

After receiving omeprazole alone or in combination with either restricted food intake or Ergocalciferol for five weeks, the chickens weighed 15–25% less (P < 0.01) at sacrifice compared to the chickens given a vehicle or fed less[2].
In comparison to either ergocalciferol alone or fasting alone, the combination of the two treatments causes more growth impairments and facial abnormalities[3].

Absorption, Distribution and Excretion
Ergocalciferol is absorbed in the intestine and carried to the liver in chylomicrons. Its intestinal absorption does not present limitations unless the presence of conditions related to fat malabsorption. However, for absorption to take place, the presence of bile is required.
The active form of ergocalciferol, calcitrol, cannot be maintained for long periods in storage tissue mainly in periods of dietary or UVB deprivation. Therefore, ergocalciferol and its metabolites are excreted via the bile with a minor contribution of renal elimination. This major fecal elimination is explained due to the cubilin-megalin receptor system-mediated renal reuptake of vitamin D metabolites bound to vitamin D binding protein.
The amount of circulating ergocalciferol is very limited as this compound is rapidly stored in fat tissue such as adipose tissue, liver and muscle. This is very obvious in reports that indicate that circulating ergocalciferol is significantly reduced in obese patients.
There are no formal reports regarding the clearance rate of ergocalciferol. Due to the structural similarity, it is recommended to consult this parameter with [cholecalciferol]. On the other hand, the proposed renal clearance of calcitriol is of 31 ml/min.
Both vitamin D2 & vitamin D3 are absorbed from the small intestine, although vitamin D3 may be absorbed more efficiently. The exact portion of the gut that is most effective in vitamin D absorption reflects the vehicle in which the vitamin is dissolved. Most of the vitamin appears first within chylomicrons in lymph.
The presence of bile is required for absorption of ergocalciferol and the extent of GI absorption may be decreased in patients with hepatic, biliary, or GI disease (e.g., Crohn's disease, Whipple's disease, sprue).
A longitudinal, randomized, double blind, placebo controlled study was conducted for 6 months to monitor ultraviolet B light exposure in human milk-fed infants both with and without supplemental vitamin D2, and to measure longitudinally the bone mineral content, growth, and serum concentrations of calcium, phosphorus, 25-hydroxyvitamin D3, 25-hydroxyvitamin D2, 1,25-dihydroxyvitamin D, and parathyroid hormone. Sequential sampling was performed of 46 human milk-fed white infants; 24 received 400 IU/day of vitamin D2, and 22 received placebo. An additional 12 patients were followed who received standard infant formula. 83% of patients completed a full 6 months of the study. Ultraviolet B light exposure and measurements of growth did not differ between groups. At 6 months, the human milk groups did not differ significantly in bone mineral content or serum concentrations of parathyroid hormone or 1,25-dihydroxyvitamin D, although total 25-hydroxyvitamin D values were significantly less in the unsupplemented human milk group (23.53 + or - 9.94 vs 36.96 + or - 11.86 ng/ml; p< 0.01). However, 25-hydroxyvitamin D3 serum concentrations were significantly higher in the unsupplemented human milk-fed group compared with the supplemented group (21.77 + or - 9.73 vs 11.74 + or - 10.27 ng/ml, p< 0.01) by 6 months of age. It was concluded that unsupplemented, human milk-fed infants had no evidence of vitamin D deficiency during the first 6 months of life.
A comparison was made of the ability of ergocalciferol and cholecalciferol to elevate plasma concentrations of vitamin D and 25-hydroxyvitamin D in cats. Cholecalciferol, given as an oral bolus in oil, resulted in a rapid elevation of plasma concentration of cholecalciferol followed by a rapid decline. In contrast, 25-hydroxyvitamin D concentration in plasma increased until day 3 after administration and remained elevated for a further 5 days. When 337 microg of both cholecalciferol and ergocalciferol in oil were given as an oral bolus to 10 cats, the peak plasma concentrations of cholecalciferol and ergocalciferol occurred at 8 or 12 h after administration. Peak concentrations of cholecalciferol were over twice those of ergocalciferol (570 +/- 80 vs. 264 +/- 42 nmol/l). The area under the curve 0-169 h for cholecalciferol was also more than twice that for ergocalciferol. When ergocalciferol and cholecalciferol were administered in a parenteral oil-based emulsion, higher concentrations of 25-hydroxyvitamin D3 than 25-hydroxyvitamin D2 were maintained in plasma. When both vitamins were included in the diet in the nutritional range, plasma concentrations of 25-hydroxyvitamin D2 were 0.68 of those of 25-hydroxyvitamin D3. Discrimination against ergocalciferol by cats appears to result from differences in affinity of the binding protein for the metabolites of the two forms of vitamin D. These results indicate that cats discriminate against ergocalciferol, and use it with an efficiency of 0.7 of that of cholecalciferol to maintain plasma 25-hydroxyvitamin D concentration.
Osteoporosis diminishes the quality of life in adults with cystic fibrosis (CF). Vitamin D deficiency resulting from malabsorption may be a factor in the etiology of low bone mineral density (BMD) in patients with CF. OBJECTIVE: Absorption of oral ergocalciferol (vitamin D2) and the consequent response of 25-hydroxyvitamin D in 10 adults with CF and exocrine pancreatic insufficiency was compared with that of 10 healthy control subjects. DESIGN: In this pharmacokinetic study, CF patients and control subjects were pair-matched on age, sex, and race. Each subject consumed 2500 microg oral vitamin D2 with a meal. The CF group also took pancreatic enzymes that provided > or = 80000 U lipase. Blood samples were obtained at baseline and at 5, 10, 24, 30, and 36 h after vitamin D2 consumption to measure serum vitamin D2 and 25-hydroxyvitamin D concentrations. RESULTS: Vitamin D2 concentrations in all subjects were near zero at baseline. CF patients absorbed less than one-half the amount of oral vitamin D2 that was absorbed by control subjects (P < 0.001). Absorption by the CF patients varied greatly; 2 patients absorbed virtually no vitamin D2. The rise in 25-hydroxyvitamin D in response to vitamin D2 absorption was significantly lower over time in the CF group than in the control group (P = 0.0012). CONCLUSIONS: Vitamin D2 absorption was significantly lower in CF patients than in control subjects. These results may help explain the etiology of vitamin D deficiency in CF patients, which may contribute to their low BMD.

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Metabolism / Metabolites
Ergocalciferol is inactive and hence, the first step in the body is ruled by the conversion of this parent compound to 25-hydroxyvitamin D by the action of CYP2R1 followed by the generation of the major circulating metabolite, 1,25-dihydroxyvitamin D or calcitrol. The generation of this major metabolite is ruled by the activity of CYP27B1 which is a key 1-hydroxylase and CYP24A1 which is responsible for the 25-hydroxylation. As part of the minor metabolism, ergocalciferol is transformed into 25-hydroxyvitamin D in the liver by the activity of D-25-hydroxylase and CYP2R1. As well, the formation of 24(R),25dihydroxyvitamin D is performed mainly in the kidneys by the action of 25-(OH)D-1-hydroxylase and 25-(OH)D-24-hydroxylase. Additionally, there are reports indicating significant activity of 3-epimerase in the metabolism of ergocalciferol which modifies the hydroxy group in C3 from the alpha position to a beta. The epimers formed seemed to have a reduced affinity for the vitamin D plasma proteins and to the vitamin D receptor. An alternative activation metabolic pathway has been reported and this process is characterized by the activity of CYP11A1 and its hydroxylation in the C-20. This 20-hydroxylated vitamin D seems to have similar biological activity than calcitriol.
Vitamin D ... is hydroxylated at the 25 position in liver to produce 25-hydroxy-vitamin D3 which is the major metabolite circulating in the plasma. The metabolite is further hydroxylated in the kidney to 1,25-dihydroxy-vitamin D3, the most active metabolite in initiating intestinal transport of calcium & phosphate & mobilization of mineral from bone.
A polar, biologically active metabolite of vitamin D2, 25-hydroxyergocalciferol, which is about 1.5 times more active in curing rickets in rats, has been isolated from pig plasma.
Dihydrotachysterol is a vitamin D analog that may be regaurded as a reduction product of vitamin D2 ... Dihydrotachysterol is about 1/450 as active as vitamin D in the antirachitic assay, but at high doses it is much more effective than vitamin D in mobilizing bone mineral.
Vitamin D2 has known human metabolites that include Vitamin D2 3-glucuronide.
Within the liver, ergocalciferol is hydroxylated to ercalcidiol (25-hydroxyergocalciferol) by the enzyme 25-hydroxylase. Within the kidney, ercalcidiol serves as a substrate for 1-alpha-hydroxylase, yielding ercalcitriol (1,25-dihydroxyergocalciferol), the biologically active form of vitamin D2.
Half Life: 19 to 48 hours (however, stored in fat deposits in body for prolonged periods).

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Biological Half-Life
Ergocalciferol can be found circulation for 1-2 days. This quick turnover is presented due to hepatic conversion and uptake by fat and muscle cells where it is transformed to the active form.
19 to 48 hours (however, stored in fat deposits in body for prolonged periods).

Toxicity Summary
Vitamin D2 is the form of vitamin D most commonly added to foods and nutritional supplements. Vitamin D2 must be transformed (hydroxylated) into one of two active forms via the liver or kidney. Once transformed, it binds to the vitamin D receptor that then leads to a variety of regulatory roles. Vitamin D plays an important role in maintaining calcium balance and in the regulation of parathyroid hormone (PTH). It promotes renal reabsorption of calcium, increases intestinal absorption of calcium and phosphorus, and increases calcium and phosphorus mobilization from bone to plasma. Vitamin D2 and its analogs appear to promote intestinal absorption of calcium through binding to a specific receptor in the mucosal cytoplasm of the intestine. Subsequently, calcium is absorbed through formation of a calcium-binding protein. Activated ergocalciferol increases serum calcium and phosphate concentrations, primarily by increasing intestinal absorption of calcium and phosphate through binding to a specific receptor in the mucosal cytoplasm of the intestine. Subsequently, calcium is absorbed through formation of a calcium-binding protein. 25-hydroxyergocalciferol is the intermediary metabolite of ergocalciferol. Although this metabolite exhibits 2-5 times more activity than unactivated ergocalciferol in curing rickets and inducing calcium absorption and mobilization (from bone) in animals, this increased activity is still insufficient to affect these functions at physiologic concentrations. Activated ergocalciferol stimulate resorption of bone and are required for normal mineralization of bone. Physiological doses of ergocalciferol also promotes calcium reabsorption by the kidneys, but the significance of this effect is not known.

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Toxicity Data
LD₅₀ = 23.7 mg/kg (Orally in mice); LD₅₀ = 10 mg/kg (Orally in rats ).

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Interactions
The effect of calcitriol (1,25-dihydroxyvitamin D3) on the conversion of ergocalciferol (vitamin D2) to 25-hydroxyvitamin D in 20 normal subjects receiving 2 separate doses of ergocalciferol, one with and one without concomitant administration of calcitriol is described. The concurrent administration of the 2 drugs made no difference to serum calcitriol concentrations.
The effects of glutethimide therapy, 500 mg/day, on the metabolism of vitamin D in a 77 yr old female patient who had taken an overdose of vitamin D2 are reported. Hypercalcemia in this patient was associated with raised serum concentrations of total 25-hydroxyvitamin D and total 1,25-dihydroxyvitamin D. Eight days after administration of glutethimide, plasma gamma-glutamyltransferase activity rose above the upper limit of normal, peaking at 90 IU/L on days 18-22 of therapy. The plasma calcium concentration fell to within the normal range on day 13. The serum concentration of 1,25-dihydroxyvitamin D began to fall within 4 days, and after 8 days it was near the lower limit of the reference range, at 70 pmol/L. The serum concentration of total 25-hydroxyvitamin D did not change appreciably until hepatic enzymes were induced; thereafter it fell gradually. Although the 25-hydroxyvitamin D concentration remained high, the concentration of 1,25-dihydroxyvitamin D did not rise again but remained within the lower part of the normal range.
The effect of a high cholesterol diet and corticosteroids on the toxicity of vitamin D2 in rats was studied. Vitamin D2 was administered orally at the dosage of 5X10+4 to 60X10+4 IU/kg, once daily for 4 days. Animals fed cholesterol showed a decrease in mortality due to vitamin D2 treatment. Dietary cholesterol inhibited toxic responses such as a diminished growth rate following anorexia, elevated serum calcium level and calcium deposition in tissues, which were produced by a sublethal dose of vitamin D2 (20X10+4 IU/kg, once daily for 4 days). Animals pretreated with the high cholesterol diet from 2 wk before the first vitamin D2 administration showed much more symptomatic relief than those given this diet after the first vitamin D2 administration. On the other hand, dexamethasone as well as corticosterone remarkably increased the mortality due to vitamin D2. The degree of vitamin D2 toxicity, enhanced by dexamethasone, was correlated with the degree of hypercalcemia and tissue calcification. Therefore, the inhibitory effect of cholesterol is not likely to be due to activation of the cholesterol corticosterone system in the adrenal gland.
The effect of short term treatment with pharmacological doses of vitamin D2 or vitamin D3 on the serum concentration of 1,25(OH)2D metabolites was examined in epileptic patients on chronic anticonvulsant drug therapy. Nine patients were studied before and after treatment with vitamin D2 4000 IU daily for 24 wk and 10 before and after treatment with vitamin D3 in the same dose. Before treatment the serum concentrations of 1,25(OH)2D and 25(OH)D were significantly lower in epileptics than in normal subjects (p< 0.01). Vitamin D2 treatment increased the serum concentration of 1,25(OH)2D2, but a corresponding decrease in 1,25(OH)2D3 resulted in an unchanged serum concentration of total 1,25(OH)2D. The serum concentration of 25(OH)D2 and 25(OH)D increase significantly, whereas there was a small decrease in 25(OH)D3. Vitamin D3 treatment did not change the serum concentration of 1,25(OH)2D3 whereas serum 25(OH)D3 increased significantly. The correlation between the serum ratio of 1,25(OH)2D2/1,25(OH)2D3 and 25(OH)D2/25(OH)D3 estimated on vitamin D2 treated epileptic patients and normal subjects was highly significant (p< 0.01). The data indicate that the serum concentration of 1,25(OH)2D2 and 1,25(OH)2D3 are directly proportional to the amount of their precursors 25(OH)D2 and 25(OH)D3 and that the concentration of total 1,25(OH)2D is tightly regulated.
Vitamin D analogs should be administered with caution in patients receiving cardiac glycosides, because hypercalcemia in these patient may result in cardiac arrhythmias. Vitamin D analogs should also be used with caution in patients with increased sensitivity to these drugs. /Vitamin D analogs/

[1]. Ergocalciferol and cholecalciferol in CKD. Am J Kidney Dis. 2012 Jul;60(1):139-56.

[2]. Chicken parathyroid hormone gene expression in response to gastrin, omeprazole, ergocalciferol, and restricted food intake. Calcif Tissue Int. 1997 Sep;61(3):210-5.

[3]. Growth retardation induced in rat fetuses by maternal fasting and massive doses of ergocalciferol. J Nutr. 1987 Feb;117(2):342-8.

Therapeutic Uses
MEDICATION (VET): ... Recommended for prophylaxis of milk fever in cows. ... Prevent atrophic rhinitis in pigs. ... Aid fracture healing in cats and dogs.
MEDICATION (VET): To be effective ... supplementation with Ca & PO4. ... Fish meals & irradiated yeast may be used as supplemental ... source. ... Diets are routinely supplemented ... 1400-1600 IU/kg. Therapy for rickets ... Level 10-20 times daily requirement, alternate days for 1 wk. /Vitamin D/
In adults and children with nutritional rickets or osteomalacia and normal GI absorption, oral administration of ... ergocalciferol daily results in normal serum calcium and phosphate concentrations in about 10 days, radiographic evidence of healing of bone within 2-4 wk, and complete healing in about 6 months. ... Diet should be corrected and, after healing has occurred, supplemental doses of ergocalciferol may be discontinued in patients with normal GI absorption. In adults with severe malabsorption and vitamin D deficiency, /daily/ dosages ... have been given to correct osteomalacia. In children with malabsorption, oral ergocalciferol dosages ... have been recommended. In vitamin D-deficient infants with tetany and rickets, calcium should be administered orally or iv to control tetany. Vitamin D deficiency is then treated orally with /a daily dose/ of ergocalciferol ... until the bones have healed, ... .
In adults with Fanconi syndrome, oral ergocalciferol .. have been given along with treatment of acidosis. In children with Fanconi syndrome oral ergocalciferol ... have been used.
For more Therapeutic Uses (Complete) data for VITAMIN D2 (11 total), please visit the HSDB record page.

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Drug Warnings
... Ergocalciferol should be administered with extreme caution, if at all, to patients with impaired renal function and with extreme caution in patient with heart disease, renal stones, or arterioscleroses.
Initial signs and symptoms ... consists of weakness, fatigue, lassitude, headache, nausea, vomiting, and diarrhea. Obtundation and coma may develop. Early impairment of renal function from hypercalcemia is manifest by polyuria, polydipsia, nocturia, decreased urinary concentration ability, and proteinuria.

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Pharmacodynamics
After the activation of the vitamin D receptor, some of the biological changes produced by ergocalciferol include mobilization and accretion of calcium and phosphorus in the bone, absorption of calcium and phosphorus in the intestine, and reabsorption of calcium and phosphorus in the kidney. Some other effects known to be produced due to the presence of vitamin D are osteoblast formation, fetus development, induction of pancreatic function, induction of neural function, improvement of immune function, cellular growth and cellular differentiation. When compared to its vitamin D counterpart [cholecalciferol], ergocalciferol has been shown to present a reduced induction of calcidiol and hence, it is less potent. Ergocalciferol supplementation in patients with end-stage renal disease has been shown to generate a significant benefit in lab parameters of bone and mineral metabolism as well as improvement in glycemic control, serum albumin levels and reduced levels of inflammatory markers.

C28H44O

396.65

396.339

C, 84.79; H, 11.18; O, 4.03

50-14-6

5,6-trans-Vitamin D2;51744-66-2;(R)-Vitamin D2;116559-84-3;Vitamin D2-d6;1311259-89-8

5280793

White to off-white solid powder

1.0±0.1 g/cm3

504.2±29.0 °C at 760 mmHg

114-118 °C(lit.)

218.2±16.5 °C

0.0±2.9 mmHg at 25°C

1.530

9.56

1

1

5

29

678

6

[C@]1(CC[C@]2([H])[C@@]1(CCC/C/2=C\C=C1/C(CC[C@H](O)C/1)=C)C)([C@H](C)/C=C/[C@H](C)C(C)C)[H]

MECHNRXZTMCUDQ-RKHKHRCZSA-N

InChI=1S/C28H44O/c1-19(2)20(3)9-10-22(5)26-15-16-27-23(8-7-17-28(26,27)6)12-13-24-18-25(29)14-11-21(24)4/h9-10,12-13,19-20,22,25-27,29H,4,7-8,11,14-18H2,1-3,5-6H3/b10-9+,23-12+,24-13-/t20-,22+,25-,26+,27-,28+/m0/s1

(1S,3Z)-3-[(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-methylidenecyclohexan-1-ol

Viosterol; Vitamin D2; Ergocalciferol; Ercalciol; calciferol

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). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.  (3). 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)

DMSO: ~31.3 mg/mL (78.8 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.24 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 20.8 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: 2.08 mg/mL (5.24 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (5.24 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 20.8 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.)