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Identification
NameParicalcitol
Accession NumberDB00910  (APRD01165)
Typesmall molecule
Groupsapproved, investigational
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
SynonymsNot Available
SaltsNot Available
Brand names
NameCompany
ZemplarNot Available
Brand mixturesNot Available
CategoriesNot Available
CAS number131918-61-1
WeightAverage: 416.6365
Monoisotopic: 416.329045274
Chemical FormulaC27H44O3
InChI KeyBPKAHTKRCLCHEA-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
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(O)(C)C
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassLipids
ClassSteroids and Steroid Derivatives
SubclassVitamin D and Derivatives
Direct parentVitamin D and Derivatives
Alternative parentsSesterterpenes; Cyclohexanols; Tertiary Alcohols; Cyclic Alcohols and Derivatives; Polyamines
Substituentscyclohexanol; tertiary alcohol; cyclic alcohol; secondary alcohol; polyamine; alcohol
Classification descriptionThis compound belongs to the vitamin d and derivatives. These are compounds containing a secosteroid backbone, usually secoergostane or secocholestane.
Pharmacology
IndicationFor treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD) Stage 3 and 4
PharmacodynamicsSecondary 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 actionParicalcitol 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.
AbsorptionWell 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 binding99.8% (bound to plasma proteins)
Metabolism

Metabolized by multiple hepatic and non-hepatic enzymes, including mitochondrial CYP24, as well as CYP3A4 and UGT1A4

Route of eliminationParicalcitol is excreted primarily by hepatobiliary excretion.
Half life4 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]
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.9971
Blood Brain Barrier + 0.795
Caco-2 permeable + 0.776
P-glycoprotein substrate Substrate 0.7667
P-glycoprotein inhibitor I Non-inhibitor 0.7431
P-glycoprotein inhibitor II Non-inhibitor 0.8491
Renal organic cation transporter Non-inhibitor 0.8292
CYP450 2C9 substrate Non-substrate 0.7968
CYP450 2D6 substrate Non-substrate 0.8903
CYP450 3A4 substrate Substrate 0.7662
CYP450 1A2 substrate Non-inhibitor 0.8127
CYP450 2C9 substrate Non-inhibitor 0.8277
CYP450 2D6 substrate Non-inhibitor 0.948
CYP450 2C19 substrate Non-inhibitor 0.8491
CYP450 3A4 substrate Non-inhibitor 0.8409
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.6631
Ames test Non AMES toxic 0.9116
Carcinogenicity Non-carcinogens 0.9111
Biodegradation Not ready biodegradable 0.988
Rat acute toxicity 4.4277 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9069
hERG inhibition (predictor II) Non-inhibitor 0.8015
Pharmacoeconomics
Manufacturers
  • Abbott laboratories pharmaceutical products div
  • Abbott laboratories
Packagers
Dosage forms
FormRouteStrength
SolutionIntravenous
Prices
Unit descriptionCostUnit
Zemplar 4 mcg capsule37.58USDcapsule
Zemplar 5 mcg/ml vial28.03USDml
Zemplar 2 mcg capsule18.79USDcapsule
Zemplar 2 mcg/ml vial11.22USDml
Zemplar 1 mcg capsule9.39USDcapsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States61367991998-10-082018-10-08
United States52469251995-04-172012-04-17
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP4.5Not Available
Predicted Properties
PropertyValueSource
water solubility6.80e-03 g/lALOGPS
logP5.27ALOGPS
logP4.26ChemAxon
logS-4.8ALOGPS
pKa (strongest acidic)14.81ChemAxon
pKa (strongest basic)-1ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count3ChemAxon
hydrogen donor count3ChemAxon
polar surface area60.69ChemAxon
rotatable bond count5ChemAxon
refractivity127.95ChemAxon
polarizability51.11ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveYesChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Anchel Schwartz, Alexei Ploutno, Koby Wolfman, “Preparation of paricalcitol.” U.S. Patent US20070149489, issued June 28, 2007.

US20070149489
General ReferenceNot Available
External Links
ResourceLink
KEGG DrugD00930
KEGG CompoundC08127
PubChem Compound5281104
PubChem Substance46505780
ChemSpider4444552
ChEBI7931
ChEMBLCHEMBL1200622
Therapeutic Targets DatabaseDAP000211
PharmGKBPA450798
Drug Product Database2266202
RxListhttp://www.rxlist.com/cgi/generic4/zemplar_caps.htm
Drugs.comhttp://www.drugs.com/cdi/paricalcitol.html
ATC CodesH05BX02
AHFS Codes
  • 88:16.00
PDB EntriesNot Available
FDA labelshow(447 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
CholecalciferolVitamin D analogs may enhance the adverse/toxic effect of other Vitamin D analogs. Avoid combined use of multiple vitamin D analogs (at pharmacologic doses). Prescribing information for calcitriol, doxercalciferol, paricalcitol, and alfacalcidol each specifically cautions against such combined use. Though not specified in the prescribing information for calcipotriene, cholecalciferol, and ergocalciferol, each contains warnings regarding the potential for vitamin D toxicity.
ColesevelamBile acid sequestrants such as colesevelam may decrease the serum concentration of Vitamin D Analogs. More specifically, bile acid sequestrants may impair absorption of Vitamin D Analogs. Avoid concomitant administration of vitamin D analogs and bile acid sequestrants (e.g., cholestyramine). Monitor plasma calcium concentrations in patients receiving combined therapy with these agents. This is particularly important in patients receiving higher doses of a bile acid sequestant (i.e., 30 g/day or more of cholestyramine or equivalent) or in patients experiencing bile acid sequestrant-induced steatorrhea. Specific recommendations regarding the separation of administration of these agents are not defined; however, it would seem prudent to separate the administration of these agents by several hours to minimize the potential risk of interaction. Similar precautions do not apply to parenterally administered vitamin D analogs.
Food InteractionsNot Available

Targets

1. Vitamin D3 receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Vitamin D3 receptor P11473 Details

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. 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial Q07973 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

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

3. UDP-glucuronosyltransferase 1-4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-4 P22310 Details

References:

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

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12