vitamin D receptor

Comparing cells in HP medium with paricalcitol (3×10-8 M; HP + PC), a significant decrease in calcification was noted. Nuclear β-catenin is reduced by paricalcitol to levels comparable to those in control cells [1].

In TAC-pari mice, paricalcitol (300 ng/kg/day) significantly lowers the mRNA expression of ANP, fibronectin, and collagen III, and prevents LV dysfunction [2].

Paricalcitol, a selective vitamin D receptor activator that activates the VDR, is administered to a subgroup of mice following TAC or sham surgery at a final dose of 300 ng/kg/day. A solution of 95% propylene glycol and 5% ethyl alcohol is used to dissolve paricalcitol. For five weeks in a row, mice receive three intraperitoneal injections of paricalcitol (or vehicle alone) on Mondays, Wednesdays, and Fridays. Included is a well-known anti-hypertrophic and anti-fibrotic medication called losartan, an angiotensin II receptor blocker (ARB). Losartan dissolved in drinking water at a concentration of 30 mg/kg/day has been demonstrated to be both feasible and effective in earlier experiments; mice are treated for five weeks in a row. Thus, eight groups in total are investigated. Ten individuals were involved in the study: Sham (n = 10), TAC (n = 10), Sham + losartan (Sham-los, n = 10), TAC + losartan (TAC-los, n = 10), Sham + paricalcitol (Sham-pari, n = 10), TAC + paricalcitol (TAC-pari, n = 10), Sham + paricalcitol + losartan (Sham-combi, n=10) and TAC + paricalcitol + losartan (TAC-combi, n = 10).

Absorption, Distribution and Excretion
Well absorbed
Paricalcitol is excreted primarily by hepatobiliary excretion.
30.8 ± 7.5 L [CKD Stage 5-HD]
34.9 ± 9.5 L [CKD Stage 5-PD]
23.8 L [healthy subjects]
1.49 +/- 0.60 L/h [chronic kidney disease Stage 5 with hemodialysis]
1.54 +/- 0.95 L/h [chronic kidney disease Stage 5with peritoneal dialysis]
Stored mainly in liver and other fat depots. /Vitamin D and analogs/
Many vitamin D analogs are readily absorbed from the GI tract following oral administration if fat absorption is normal. 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). Because vitamin D is fat soluble, it is incorporated into chylomicrons and absorbed via the lymphatic system; approximately 80% of ingested vitamin D appears to be absorbed systemically through this mechanism, principally in the small intestine. Although some evidence suggested that intestinal absorption of vitamin D may be decreased in geriatric adults, other evidence did not show clinically important age-related alterations in GI absorption of the vitamin in therapeutic doses. It currently is not known whether aging alters the GI absorption of physiologic amounts of vitamin D. /Vitamin D analogs/
It is not known whether paricalcitol ... is excreted in human milk.
In healthy subjects, plasma radioactivity after a single 0.16 mg/kg intravenous bolus dose of 3H-paricalcitol (n=4) was attributed to parent drug. Paricalcitol was eliminated primarily by hepatobiliary excretion, as 74% of the radioactive dose was recovered in feces and only 16% was found in urine.
For more Absorption, Distribution and Excretion (Complete) data for PARICALCITOL (7 total), please visit the HSDB record page.

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Metabolism / Metabolites
Metabolized by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4
After oral administration of a 0.48 mcg/kg dose of 3 H-paricalcitol, parent drug was extensively metabolized, with only about 2% of the dose eliminated unchanged in the feces, and no parent drug found in the urine. Several metabolites were detected in both the urine and feces. Most of the systemic exposure was from the parent drug. Two minor metabolites, relative to paricalcitol, were detected in human plasma. One metabolite was identified as 24(R)-hydroxy paricalcitol, while the other metabolite was unidentified. The 24(R)-hydroxy paricalcitol is less active than paricalcitol in an in vivo rat model of PTH suppression.
In vitro data suggest that paricalcitol is metabolized by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4. The identified metabolites include the product of 24(R)-hydroxylation, 24,26- and 24,28-dihydroxylation and direct glucuronidation.

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Biological Half-Life
4 to 6 hours
In healthy subjects, the mean elimination half-life of paricalcitol is 4 to 6 hours over the studied dose range of 0.06 to 0.48 mcg/kg. The pharmacokinetics of paricalcitol capsule have been studied in patients with chronic kidney disease (CKD) Stage 3 and 4 patients. After administration of 4 mcg paricalcitol capsule in CKD Stage 3 patients, the mean elimination half-life of paricalcitol is 17 hours. The mean half-life of paricalcitol is 20 hours in CKD Stage 4 patients when given 3 mcg of paricalcitol capsule.
Plasma half-life: 15 hours.

Protein Binding
99.8% (bound to plasma proteins)

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Interactions
Corticosteroids counteract the effects of vitamin D analogs. /Vitamin D analogs/
Digitalis toxicity is potentiated by hypercalcemia of any cause, so caution should be applied when digitalis compounds are prescribed concomitantly with /paricalcitol/. Adynamic bone lesions may develop if PTH levels are suppressed to abnormal levels.
Concurrent administration of thiazide diuretics and pharmacologic doses of vitamin D analogs in patients with hypoparathyroidism may result in hypercalcemia which may be transient and self-limited or may require discontinuance of vitamin D analogs. Thiazide-induced hypercalcemia in hypoparathyroid patients is probably caused by increased release of calcium from bone. /Vitamin D analogs/
Excessive use of mineral oil may interfere with intestinal absorption of vitamin D analogs. /Vitamin D analogs/
For more Interactions (Complete) data for PARICALCITOL (9 total), please visit the HSDB record page.

[1]. Martinez-Moreno JM, et al. In vascular smooth muscle cells paricalcitol prevents phosphate-induced Wnt/beta-catenin activation. Am J Physiol Renal Physiol. 2012 Aug 8.
[2]. Meems LM, et al. The vitamin D receptor activator paricalcitol prevents fibrosis and diastolic dysfunction in a murine model of pressure overload. J Steroid Biochem Mol Biol. 2012 Jul 16;132(3-5):282-289

Paricalcitol is a seco-cholestane and a hydroxy seco-steroid. It has a role as an antiparathyroid drug. It is functionally related to a vitamin D2.
Paricalcitol is a synthetic vitamin D analog. Paricalcitol has been used to reduce parathyroid hormone levels. Paricalcitol is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure.
Paricalcitol is a Vitamin D2 Analog and Vitamin D Analog.
Paricalcitol is a synthetic noncalcemic, nonphosphatemic vitamin D analogue. Paricalcitol binds to the vitamin D receptor and has been shown to reduce parathyroid hormone (PTH) levels. This agent also increases the expression of PTEN ('Phosphatase and Tensin homolog deleted on chromosome Ten'), a tumor-suppressor gene, in leukemic cells and cyclin-dependent kinase inhibitors, resulting in tumor cell apoptosis and tumor cell differentiation into normal phenotypes. (NCI04)

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Drug Indication
For treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD) Stage 3 and 4
FDA Label

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Mechanism of Action
Paricalcitol is a synthetic, biologically active vitamin D analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring. Preclinical andin vitro studies have demonstrated that paricalcitol's biological actions are mediated through binding of the VDR, which results in the selective activation of vitamin D responsive pathways. Vitamin D and paricalcitol have been shown to reduce parathyroid hormone levels by inhibiting PTH synthesis and secretion.
Paricalcitol is a synthetic, biologically active vitamin D analog of calcitriol with modifications to the side chain (D2) and the A (19-nor) ring. Preclinical and in vitro studies have demonstrated that paricalcitol's biological actions are mediated through binding of the vitamin D receptor (VDR), which results in the selective activation of vitamin D responsive pathways. Vitamin D and paricalcitol have been shown to reduce parathyroid hormone levels by inhibiting PTH synthesis and secretion.

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Therapeutic Uses
Paricalcitol is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD) Stage 3 and 4. /Included in US product labeling/
Therapeutic doses of specific vitamin D analogs are used in the treatment of chronic hypocalcemia, hypophosphatemia, rickets, and osteodystrophy associated with various medical conditions including chronic renal failure, familial hypophosphatemia, and hypoparathyroidism (postsurgical or idiopathic, or pseudohypoparathyroidism). Some analogs have been found to reduct elevated parathyroid hormone concentrations in patients with renal osteodystrophy associated with hyperparathyroidism. Theoretically, any of the vitamin D analogs may be used for the above conditions, However, because of their pharmacologic properties, some may be more useful in certain situations than others. Alfacalcidol, calcitriol, and dihydrotachysterol are usually preferred in patients with renal failure since these patients have impaired ability to synthesize calcitriol from cholecalciferol and ergocalciferol; therefore, the response is more predictable. In addition, their shorter half-lives may make toxicity easier to manage (hypercalcemia reverses more quickly). Ergocalciferol may not be the preferred agent in the treatment of familial hypophosphatemia or hypoparathyroidism because the large doses needed are associated with a risk of overdose and hypercalcemia; dihydrotachysterol and calcitriol may be preferred. /Included in US product labeling/

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Drug Warnings
/Paricalcitol/ should not be given to patients with evidence of vitamin D toxicity, hypercalcemia, or hypersensitivity to any ingredient in this product.
Doses of vitamin D analogs that do not exceed the physiologic requirement are usually nontoxic. However, some infants and patients with sarcoidosis or hypoparathyroidism may have increased sensitivity to vitamin D analogs. /Vitamin D analogs/
Acute or chronic administration of excessive doses of vitamin D analogs or enhanced responsiveness to physiologic amounts of ergocalciferol or cholecalciferol may lead to hypervitaminosis D manifested by hypercalcemia. /Vitamin D analogs/
Decreased renal function without hypercalcemia has also been reported in patients with hypoparathyroidism after long-term vitamin D analog therapy. Before therapy with vitamin D analogs is initiated, serum phosphate concentrations must be controlled. To avoid ectopic calcification, the serum calcium (in mg/dL) times phosphorus (in mg/dL) should not be allowed to exceed 70. Because administration of vitamin D analogs may increase phosphate absorption, patients with renal failure may require adjustment in the dosage of aluminum-containing antacids used to decrease phosphate absorption. /Vitamin D analogs/
For more Drug Warnings (Complete) data for PARICALCITOL (8 total), please visit the HSDB record page.

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Pharmacodynamics
Secondary hyperparathyroidism is characterized by an elevation in parathyroid hormone (PTH) associated with inadequate levels of active vitamin D hormone. The source of vitamin D in the body is from synthesis in the skin and from dietary intake. Vitamin D requires two sequential hydroxylations in the liver and the kidney to bind to and to activate the vitamin D receptor (VDR). The endogenous VDR activator, calcitriol [1,25(OH)2 D3], is a hormone that binds to VDRs that are present in the parathyroid gland, intestine, kidney, and bone to maintain parathyroid function and calcium and phosphorus homeostasis, and to VDRs found in many other tissues, including prostate, endothelium and immune cells. VDR activation is essential for the proper formation and maintenance of normal bone. In the diseased kidney, the activation of vitamin D is diminished, resulting in a rise of PTH, subsequently leading to secondary hyperparathyroidism and disturbances in the calcium and phosphorus homeostasis.1 Decreased levels of 1,25(OH)2 D3 have been observed in early stages of chronic kidney disease. The decreased levels of 1,25(OH)2 D3 and resultant elevated PTH levels, both of which often precede abnormalities in serum calcium and phosphorus, affect bone turnover rate and may result in renal osteodystrophy. An in vitro study indicates that paricalcitol is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A at concentrations up to 50 nM (21 ng/mL).

C27H44O3

416.63646

416.329

C, 77.83; H, 10.64; O, 11.52

131918-61-1

131918-61-1

5281104

White, crystalline powder

1.1±0.1 g/cm3

564.8±50.0 °C at 760 mmHg

238.3±24.7 °C

0.0±3.5 mmHg at 25°C

1.609

5.83

3

3

5

30

676

7

C[C@]([C@]([C@H](C)/C=C/[C@H](C)C(C)(C)O)([H])CC1)(CCC/2)[C@]1([H])C2=C\C=C3C[C@@H](O)C[C@H](O)C/3

BPKAHTKRCLCHEA-UBFJEZKGSA-N

InChI=1S/C27H44O3/c1-18(8-9-19(2)26(3,4)30)24-12-13-25-21(7-6-14-27(24,25)5)11-10-20-15-22(28)17-23(29)16-20/h8-11,18-19,22-25,28-30H,6-7,12-17H2,1-5H3/b9-8+,21-11+/t18-,19+,22-,23-,24-,25+,27-/m1/s1

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

paricalcitol-d6; Paricalcitol; Compound 49510; 19-Nor-1alpha,25-dihydroxyvitamin D2; Paracalcin; Abbott brand of paricalcitol; Zemplar

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: 83~100 mg/mL (199.2~240.0 mM)
Ethanol: 12.5~13 mg/mL (30~31.2 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.00 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.)