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
Absorption is good Palicalcitol is primarily excreted via the liver and gallbladder. 30.8 ± 7.5 L [CKD Stage 5 - Hemodialysis] 34.9 ± 9.5 L [CKD Stage 5 - Peritoneal Dialysis] 23.8 L [Healthy Subjects] 1.49 ± 0.60 L/h [CKD Stage 5 Hemodialysis Patients] 1.54 ± 0.95 L/h [CKD Stage 5 Peritoneal Dialysis Patients] It is mainly stored in the liver and other adipose tissues. /Vitamin D and its analogues/ Many vitamin D analogues are readily absorbed by the gastrointestinal tract after oral administration if fat absorption is normal. The presence of bile is necessary for ergocalcitol absorption, and gastrointestinal absorption may be reduced in patients with liver, biliary tract, or gastrointestinal diseases (e.g., Crohn's disease, Whipple's disease, celiac disease). 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, primarily in the small intestine. While some evidence suggests that intestinal absorption of vitamin D may be reduced in older adults, other evidence has not shown clinically significant age-related changes in gastrointestinal absorption of vitamin D at therapeutic doses. It is currently unclear whether aging alters gastrointestinal absorption of physiological doses of vitamin D. /Vitamin D Analogs/
It is unclear whether paricalcitol is excreted into human milk.
In healthy subjects, plasma radioactivity following a single intravenous injection of 0.16 mg/kg 3H-paricalcitol (n=4) was attributed to the parent drug. Paricalcitol is primarily eliminated via hepatobiliary excretion, with 74% of the radioactive dose recovered in feces and only 16% detected in urine.
For more complete data on absorption, distribution, and excretion of paricalcitol (7 in total), please visit the HSDB records page. Metabolites/Metabolites: Metabolized by a variety of hepatic and non-hepatic enzymes, including mitochondrial CYP24, CYP3A4, and UGT1A4. Following oral administration of 0.48 mcg/kg of 3H-paricalcitol, the parent drug is extensively metabolized, with only approximately 2% of the dose excreted unchanged in feces; the parent drug was not detected in urine. Several metabolites were detected in both urine and feces. The majority of systemic exposure is from the parent drug. Two minor metabolites relative to paricalcitol were detected in human plasma. One metabolite was identified as 24(R)-hydroxyparicalcitol, while the other has not been identified. In an in vivo rat model of parathyroid hormone suppression, 24(R)-hydroxyparicalcitol showed lower activity than paricalcitol. In vitro data indicate that paricalcitol is metabolized by a variety of hepatic and non-hepatic enzymes, including mitochondrial CYP24, CYP3A4, and UGT1A4. Identified metabolites include 24(R)-hydroxylated products, 24,26- and 24,28-dihydroxylated products, and direct glucuronidation products.
Biological Half-Life
4 to 6 hours
In healthy subjects, the mean elimination half-life of paricalcitol in the study dose range of 0.06 to 0.48 mcg/kg is 4 to 6 hours. The pharmacokinetics of paricalcitol capsules have been studied in patients with chronic kidney disease (CKD) stages 3 and 4. In CKD stage 3 patients, the mean elimination half-life of paricalcitol after administration of 4 mcg paricalcitol capsules was 17 hours. In CKD stage 4 patients, the mean half-life of paricalcitol after administration of 3 mcg paricalcitol capsules was 20 hours.
Plasma half-life: 15 hours.

Protein Binding
99.8% (bound to plasma proteins) Interactions Corticosteroids can antagonize the effects of vitamin D analogs. /Vitamin D Analogs/ Hypercalcemia from any cause can enhance digitalis toxicity; therefore, caution should be exercised when digitalis compounds are taken concurrently with paricalcitol. Adynamic bone lesions may occur if parathyroid hormone (PTH) levels are suppressed to abnormal levels. In patients with hypoparathyroidism, concomitant use of thiazide diuretics and pharmacological doses of vitamin D analogs may lead to hypercalcemia, which may be transient, self-limiting, or may require discontinuation of vitamin D analogs. Hypercalcemia induced by thiazide diuretics in patients with hypoparathyroidism may be due to increased calcium release from bones. /Vitamin D Analogs/ Excessive use of mineral oil may interfere with the intestinal absorption of vitamin D analogs. /Vitamin D Analogs/
For more complete data on interactions of PARICALCITOL (9 in 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 an open-ring cholesterol alkyl compound and a hydroxyopen-ring steroid compound with antiparathyroid hormone activity. Its function is related to vitamin D2. Paricalcitol is a synthetic vitamin D analog used to lower parathyroid hormone levels. Paricalcitol is indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic renal failure. Paricalcitol is both a vitamin D2 analog and a vitamin D analog. Paricalcitol is a synthetic, non-calcified, non-phosphorized vitamin D analog. Paricalcitol binds to vitamin D receptors and has been shown to lower parathyroid hormone (PTH) levels. This drug can also increase the expression of the tumor suppressor gene PTEN (a homolog of phosphatase and tensin missing on chromosome 10) in leukemia cells and cyclin-dependent kinase inhibitors, thereby leading to tumor cell apoptosis and differentiation into a normal phenotype. (NCI04)

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Drug Indications
For the treatment of secondary hyperparathyroidism associated with stage 3 and 4 chronic kidney disease (CKD)
FDA Label

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Mechanism of Action
Paricalcitol is a synthetic, biologically active vitamin D analogue, a derivative of calcitriol with modified side chains (D2) and A (19-nor) rings. Preclinical and in vitro studies have shown that the biological action of paricalcitol is mediated by binding to the vitamin D receptor (VDR), thereby selectively activating the vitamin D response pathway. Vitamin D and paricalcitol have been shown to reduce PTH levels by inhibiting the synthesis and secretion of parathyroid hormone (PTH).
Paricalcitol is a synthetic, biologically active vitamin D analogue, a derivative of calcitriol with modified side chains (D2) and A (19-nor) rings. Preclinical and in vitro studies have shown that the biological action of paricalcitol is mediated by binding to the vitamin D receptor (VDR), thereby selectively activating the vitamin D response pathway. Vitamin D and paricalcitol have been shown to reduce PTH levels by inhibiting the synthesis and secretion of parathyroid hormone (PTH).

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Therapeutic Use
Paricalcitol is indicated for the prevention and treatment of secondary hyperparathyroidism associated with stages 3 and 4 of chronic kidney disease (CKD). /US Product Label Contains/
Therapeutic doses of certain vitamin D analogs are used to treat chronic hypocalcemia, hypophosphatemia, rickets, and osteodystrophy associated with a variety of conditions, including chronic renal failure, familial hypophosphatemia, and hypoparathyroidism (postoperative, idiopathic, or pseudohypoparathyroidism).
Some vitamin D analogs have been found to reduce elevated parathyroid hormone levels in patients with renal osteodystrophy accompanied by hyperparathyroidism. In theory, any vitamin D analogue can be used to treat the aforementioned conditions. However, due to their different pharmacological properties, some analogues may be more effective than others in specific situations. For patients with renal failure, alfacalcidol, calcitriol, and dihydrotachysterol are usually the first choice because these patients have impaired ability to synthesize calcitriol from cholecalciferol and ergocalciferol; therefore, their efficacy is more predictable. Furthermore, these drugs have shorter half-lives, and toxicities are easier to control (hypercalcemia reverses more quickly). Ergocalciferol may not be the first-line treatment for familial hypophosphatemia or hypoparathyroidism because the high doses required are associated with the risk of overdose and hypercalcemia; dihydrotachysterol and calcitriol may be more suitable. /US product label contains/

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Drug Warnings
Paricalciferol should not be given to patients with vitamin D poisoning, hypercalcemia, or hypersensitivity to any component of this product.
Vitamin D analogues are generally non-toxic when administered at doses not exceeding physiological requirements. However, some infants and patients with sarcoidosis or hypoparathyroidism may be more sensitive to vitamin D analogs. /Vitamin D Analogs/
Acute or chronic overdose of vitamin D analogs, or an enhanced response to physiological doses of ergocalciferol or cholecalciferol, can lead to vitamin D overdose, manifested as hypercalcemia. /Vitamin D Analogs/
Long-term use of vitamin D analogs to treat hypoparathyroidism has been reported to result in decreased renal function without hypercalcemia. Serum phosphate concentrations must be controlled before starting vitamin D analog therapy. To avoid ectopic calcification, the ratio of serum calcium (mg/dL) to phosphorus (mg/dL) should not exceed 70. Because vitamin D analogs may increase phosphate absorption, patients with renal failure may require dose adjustments of aluminum-containing antacids used to reduce phosphate absorption. /Vitamin D Analogs/
For more complete data on drug warnings for paricillin (8 of 8), please visit the HSDB record page.

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Pharmacodynamics
Secondary hyperparathyroidism is characterized by elevated parathyroid hormone (PTH) levels, accompanied by insufficient levels of active vitamin D hormone. Sources of vitamin D in the body include skin synthesis and dietary intake. Vitamin D requires two consecutive hydroxylation processes in the liver and kidneys to bind to and activate vitamin D receptors (VDRs). The endogenous vitamin D receptor (VDR) activator calcitriol [1,25(OH)₂D₃] is a hormone that binds to VDRs present in the parathyroid glands, intestines, kidneys, and bones to maintain parathyroid function and calcium-phosphorus homeostasis; it also binds to VDRs present in many other tissues, including the prostate, endothelial cells, and immune cells. VDR activation is crucial for normal bone formation and maintenance. In kidney disease, weakened vitamin D activation leads to elevated parathyroid hormone (PTH) levels, which in turn causes secondary hyperparathyroidism and calcium-phosphorus homeostasis disturbances. ¹ Decreased 1,25(OH)₂D₃ levels have been observed in the early stages of chronic kidney disease. Decreased 1,25(OH)₂D₃ levels and the resulting increased PTH levels (both usually precede serum calcium and phosphorus abnormalities) affect bone turnover and may lead to renal osteodystrophy. In vitro studies have shown that paricalcitol does not inhibit 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.)