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Identification
Name Paricalcitol
Accession Number DB00910 (APRD01165)
Type small molecule
Groups approved
Description

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.
Structure Thumb
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Display: 2D Structure | 3D Structure
Synonyms
  • paricalcitol
Brand names
  • Zemplar
Brand name mixtures Not Available
Categories Not Available
CAS number 131918-61-1
Weight Average: 416.6365
Monoisotopic: 416.329045274
Chemical Formula C27H44O3
InChI Key InChIKey=BPKAHTKRCLCHEA-UBFJEZKGSA-N
InChI
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
Plain Text
IUPAC Name
(1R,3R)-5-{2-[(1R,3aS,4E,7aR)-1-[(2R,3E,5S)-6-hydroxy-5,6-dimethylhept-3-en-2-yl]-7a-methyl-octahydro-1H-inden-4-ylidene]ethylidene}cyclohexane-1,3-diol
SMILES
[H]C1CC[C@]2(C)[C@]([H])(CC[C@@]2([H])\C1=C\C=C1C[C@@H](O)C[C@H](O)C1)[C@H](C)\C=C\[C@H](C)C(C)(C)O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Alcohols and Polyols
Substructures
  • Hydroxy Compounds
  • Alkanes and Alkenes
  • Alcohols and Polyols
Pharmacology
Indication For treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD) Stage 3 and 4
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).
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.
Absorption Well absorbed
Volume of distribution
  • 30.8 ± 7.5 L [CKD Stage 5-HD]
  • 34.9 ± 9.5 L [CKD Stage 5-PD]
  • 23.8 L [healthy subjects]
Protein binding 99.8% (bound to plasma proteins)
Metabolism

Metabolized by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4
Route of elimination Paricalcitol is excreted primarily by hepatobiliary excretion.
Half life 4 to 6 hours
Clearance
  • 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]
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Abbott laboratories pharmaceutical products div
  • Abbott laboratories
Packagers
Dosage forms
Form Route Strength
Solution Intravenous
Prices
Unit description Cost Unit
Zemplar 4 mcg capsule 37.58 USD capsule
Zemplar 5 mcg/ml vial 28.03 USD ml
Zemplar 2 mcg capsule 18.79 USD capsule
Zemplar 2 mcg/ml vial 11.22 USD ml
Zemplar 1 mcg capsule 9.39 USD capsule
Patents
Country Patent Number Approved Expires
United States 6136799 1998-10-08 2018-10-08
United States 5246925 1995-04-17 2012-04-17
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
logP 4.5 PhysProp
Predicted Properties
Property Value Source
water solubility 6.80e-03 g/l ALOGPS
logP 5.27 ALOGPS
logP 4.26 ChemAxon Molconvert
logS -4.79 ALOGPS
pKa 15.51 ChemAxon Molconvert
hydrogen acceptor count 3 ChemAxon Molconvert
hydrogen donor count 3 ChemAxon Molconvert
polar surface area 60.69 ChemAxon Molconvert
rotatable bond count 5 ChemAxon Molconvert
refractivity 127.95 ChemAxon Molconvert
polarizability 51.11 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D00930 Link_out
KEGG Compound C08127 Link_out
PubChem Compound 5281104 Link_out
PubChem Substance 46505780 Link_out
ChemSpider 4444552 Link_out
ChEBI 7931 Link_out
ChEMBL 7931 Link_out
Therapeutic Targets Database DAP000211 Link_out
PharmGKB PA450798 Link_out
Drug Product Database 2266202 Link_out
RxList http://www.rxlist.com/cgi/generic4/zemplar_caps.htm Link_out
Drugs.com http://www.drugs.com/cdi/paricalcitol.html Link_out
ATC Codes
  • A11CC07
AHFS Codes
  • 88:16.00
PDB Entries Not Available
FDA label show (446.6 KB)
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. Vitamin D3 receptor

Pharmacological action: yes
Actions: agonist

Nuclear hormone receptor. VDR mediates the action of vitamin D3 by controlling the expression of hormone sensitive genes

Organism class: human
UniProt ID: P11473 Link_out
Gene: VDR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. Andress DL: Vitamin D treatment in chronic kidney disease. Semin Dial. 2005 Jul-Aug;18(4):315-21. Pubmed
  4. Brancaccio D, Cozzolino M, Pasho S, Fallabrino G, Olivi L, Gallieni M: New acquisitions in therapy of secondary hyperparathyroidism in chronic kidney disease and peritoneal dialysis patients: role of vitamin D receptor activators. Contrib Nephrol. 2009;163:219-26. Epub 2009 Jun 3. Pubmed
  5. Wu-Wong JR, Nakane M, Gagne GD, Brooks KA, Noonan WT: Comparison of the pharmacological effects of paricalcitol and doxercalciferol on the factors involved in mineral homeostasis. Int J Endocrinol. 2010;2010:621687. Epub 2010 Mar 2. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Enzymes

1. Cytochrome P450 24A1, mitochondrial

Actions: substrate

Has a role in maintaining calcium homeostasis. Catalyzes the NADPH-dependent 24-hydroxylation of 25-hydroxyvitamin D(3) in the presence of adrenodoxin and NADPH-adrenodoxin reductase

UniProt ID: Q07973 Link_out
Gene: CYP24A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Robinson DM, Scott LJ: Paricalcitol: a review of its use in the management of secondary hyperparathyroidism. Drugs. 2005;65(4):559-76. Pubmed
  2. Abbott Laboratories. Zemplar® (paricalcitol) capsules prescribing information. North Chicago, IL; 2010 June.

2. Cytochrome P450 3A4

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Abbott Laboratories. Zemplar® (paricalcitol) capsules prescribing information. North Chicago, IL; 2010 June.

3. UDP-glucuronosyltransferase 1-4

Actions: substrate

UDPGT is of major importance in the conjugation and subsequent elimination of potentially toxic xenobiotics and endogenous compounds. This isoform glucuronidates bilirubin IX- alpha to form both the IX-alpha-C8 and IX-alpha-C12 monoconjugates and diconjugate

UniProt ID: P22310 Link_out
Gene: UGT1A4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Abbott Laboratories. Zemplar® (paricalcitol) capsules prescribing information. North Chicago, IL; 2010 June.
Comments
Drug created on June 13, 2005 07:24 / Updated on April 19, 2011 15:07

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.