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Identification
NameCinacalcet
Accession NumberDB01012  (APRD00872)
Typesmall molecule
Groupsapproved
Description

Cinacalcet (INN) is a drug that acts as a calcimimetic (i.e. it mimics the action of calcium on tissues) by allosteric activation of the calcium-sensing receptor that is expressed in various human organ tissues. It is sold by Amgen under the trade name Sensipar® in North America and Australia and as Mimpara® in Europe. Cinacalcet is used to treat hyperparathyroidism (elevated parathyroid hormone levels), a consequence of parathyroid tumors and chronic renal failure.

Structure
Thumb
SynonymsNot Available
SaltsNot Available
Brand names
NameCompany
SensiparNot Available
Brand mixturesNot Available
Categories
CAS number226256-56-0
WeightAverage: 357.412
Monoisotopic: 357.170434324
Chemical FormulaC22H22F3N
InChI KeyVDHAWDNDOKGFTD-MRXNPFEDSA-N
InChI
InChI=1S/C22H22F3N/c1-16(20-13-5-10-18-9-2-3-12-21(18)20)26-14-6-8-17-7-4-11-19(15-17)22(23,24)25/h2-5,7,9-13,15-16,26H,6,8,14H2,1H3/t16-/m1/s1
IUPAC Name
[(1R)-1-(naphthalen-1-yl)ethyl]({3-[3-(trifluoromethyl)phenyl]propyl})amine
SMILES
C[C@@H](NCCCC1=CC(=CC=C1)C(F)(F)F)C1=CC=CC2=CC=CC=C12
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassBenzenoids
ClassAcenes and Derivatives
SubclassNaphthalenes
Direct parentNaphthalenes
Alternative parentsPhenylpropylamines; Phenethylamines; Polyamines; Dialkylamines; Organofluorides; Alkyl Fluorides
Substituentsbenzene; secondary aliphatic amine; secondary amine; polyamine; organonitrogen compound; amine; organofluoride; organohalogen; alkyl halide; alkyl fluoride
Classification descriptionThis compound belongs to the naphthalenes. These are compounds containing a naphthalene moiety, which consists of two fused benzene rings.
Pharmacology
IndicationFor the treatment of secondary hyperparathyroidism in patients with Chronic Kidney Disease who are on hemodialysis or peritoneal dialysis. Also for the treatment of hypercalcemia in patients with parathyroid carcinoma.
PharmacodynamicsCinacalcet is a drug that acts as a calcimimetic (i.e. it mimics the action of calcium on tissues). Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is a progressive disease, associated with increases in parathyroid hormone (PTH) levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals of treatment of secondary hyperparathyroidism are to lower levels of PTH, calcium, and phosphorus in the blood, in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. In CKD patients on dialysis with uncontrolled secondary HPT, reductions in PTH are associated with a favorable impact on bone-specific alkaline phosphatase (BALP), bone turnover and bone fibrosis. Cinacalcet reduces calcium levels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium.
Mechanism of actionThe calcium-sensing receptors on the surface of the chief cell of the parathyroid gland is the principal regulator of parathyroid hormone secretion (PTH). Cinacalcet directly lowers parathyroid hormone levels by increasing the sensitivity of the calcium sensing receptors to activation by extracellular calcium, resulting in the inhibition of PTH secretion. The reduction in PTH is associated with a concomitant decrease in serum calcium levels.
AbsorptionRapidly absorbed following oral administration.
Volume of distribution
  • 1000 L
Protein bindingApproximately 93 to 97% bound to plasma proteins.
Metabolism

Metabolism is hepatic by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2. After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was rapidly and extensively metabolized via: 1) oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are further metabolized via ß-oxidation and glycine conjugation; the oxidative N-dealkylation process also generates metabolites that contain the naphthalene ring; and 2) oxidation of the naphthalene ring on the parent drug to form dihydrodiols, which are further conjugated with glucuronic acid.

SubstrateEnzymesProduct
Cinacalcet
Not Available
Hydrocinnamic acidDetails
Cinacalcet
Not Available
hydroxy-hydrocinnamic acidDetails
Route of eliminationCinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6 and CYP1A2. Renal excretion of metabolites was the primary route of elimination of radioactivity.
Half lifeTerminal half-life is 30 to 40 hours. The mean half-life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe hepatic impairment, respectively.
ClearanceNot Available
ToxicityDoses titrated up to 300 mg once daily have been safely administered to patients on dialysis. Overdosage of cinacalcet may lead to hypocalcemia.
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 + 1.0
Blood Brain Barrier + 0.9927
Caco-2 permeable + 0.7058
P-glycoprotein substrate Substrate 0.5309
P-glycoprotein inhibitor I Inhibitor 0.8512
P-glycoprotein inhibitor II Inhibitor 0.6937
Renal organic cation transporter Inhibitor 0.5305
CYP450 2C9 substrate Non-substrate 0.7761
CYP450 2D6 substrate Substrate 0.8293
CYP450 3A4 substrate Non-substrate 0.5425
CYP450 1A2 substrate Inhibitor 0.9206
CYP450 2C9 substrate Non-inhibitor 0.8572
CYP450 2D6 substrate Inhibitor 0.8188
CYP450 2C19 substrate Inhibitor 0.8795
CYP450 3A4 substrate Inhibitor 0.7166
CYP450 inhibitory promiscuity High CYP Inhibitory Promiscuity 0.5904
Ames test Non AMES toxic 0.5152
Carcinogenicity Non-carcinogens 0.8785
Biodegradation Not ready biodegradable 0.9932
Rat acute toxicity 2.8511 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9175
hERG inhibition (predictor II) Inhibitor 0.8494
Pharmacoeconomics
Manufacturers
  • Amgen inc
Packagers
Dosage forms
FormRouteStrength
TabletOral
Prices
Unit descriptionCostUnit
Sensipar 90 mg tablet44.03USDtablet
Sensipar 60 mg tablet29.35USDtablet
Sensipar 30 mg tablet14.69USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States60110681996-12-142016-12-14
United States62112441995-10-232015-10-23
Canada22028792005-08-302015-10-23
Properties
Statesolid
Experimental Properties
PropertyValueSource
water solubilitySlightly soluble (in HCl salt form)Not Available
logP6.5Not Available
Predicted Properties
PropertyValueSource
water solubility5.59e-05 g/lALOGPS
logP5.57ALOGPS
logP6.27ChemAxon
logS-6.8ALOGPS
pKa (strongest basic)10.3ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count1ChemAxon
hydrogen donor count1ChemAxon
polar surface area12.03ChemAxon
rotatable bond count7ChemAxon
refractivity100.12ChemAxon
polarizability37.9ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Revital Lifshitz-Liron, “Process for the preparation of cinacalcet base.” U.S. Patent US20070259964, issued November 08, 2007.

US20070259964
General Reference
  1. Torres PU: Cinacalcet HCl: a novel treatment for secondary hyperparathyroidism caused by chronic kidney disease. J Ren Nutr. 2006 Jul;16(3):253-8. Pubmed
  2. Padhi D, Harris R: Clinical pharmacokinetic and pharmacodynamic profile of cinacalcet hydrochloride. Clin Pharmacokinet. 2009;48(5):303-11. doi: 10.2165/00003088-200948050-00002. Pubmed
  3. Dong BJ: Cinacalcet: An oral calcimimetic agent for the management of hyperparathyroidism. Clin Ther. 2005 Nov;27(11):1725-51. Pubmed
External Links
ResourceLink
PubChem Compound156419
PubChem Substance46506315
ChemSpider137743
ChEBI48390
ChEMBLCHEMBL1201284
Therapeutic Targets DatabaseDAP000256
PharmGKBPA164776671
IUPHAR3308
Guide to Pharmacology3308
Drug Product Database2257157
RxListhttp://www.rxlist.com/cgi/generic3/sensipar.htm
Drugs.comhttp://www.drugs.com/cdi/cinacalcet.html
WikipediaCinacalcet
ATC CodesH05BX01
AHFS Codes
  • 92:00.00
PDB EntriesNot Available
FDA labelshow(278 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
ErythromycinThe macrolide, erythromycin, may increase the serum concentration and toxicity of cinacalcet.
ItraconazoleItraconazole may increase the effect and toxicity of cinacalcet.
KetoconazoleKetoconazole may increase the effect and toxicity of cinacalcet.
TamoxifenCinacalcet may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Concomitant therapy should be avoided.
TamsulosinCinacalcet, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Cinacalcet is initiated, discontinued, or dose changed.
TelithromycinTelithromycin may reduce clearance of Cinacalcet. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Cinacalcet if Telithromycin is initiated, discontinued or dose changed.
TolterodineCinacalcet may decrease the metabolism and clearance of Tolterodine. Monitor for adverse/toxic effects of Tolterodine.
TramadolCinacalcet may decrease the effect of Tramadol by decreasing active metabolite production.
TrimipramineThe strong CYP2D6 inhibitor, Cinacalcet, may decrease the metabolism and clearance of Trimipramine, a CYP2D6 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Trimipramine if Cinacalcet is initiated, discontinued or dose changed.
VenlafaxineCinacalcet, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Venlafaxine, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Venlafaxine if Cinacalcet is initiated, discontinued, or dose changed.
VoriconazoleVoriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of cinacalcet by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of cinacalcet if voriconazole is initiated, discontinued or dose changed.
ZuclopenthixolCinacalcet, a strong CYP2D6 inhibitor, may increase the serum concentration of zuclopenthixol by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zuclopenthixol if cinacalcet is initiated, discontinued or dose changed.
Zuclopenthixol acetateCinacalcet, a strong CYP2D6 inhibitor, may increase the serum concentration of zuclopenthixol by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zuclopenthixol if cinacalcet is initiated, discontinued or dose changed.
Zuclopenthixol decanoateCinacalcet, a strong CYP2D6 inhibitor, may increase the serum concentration of zuclopenthixol by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zuclopenthixol if cinacalcet is initiated, discontinued or dose changed.
Food Interactions
  • Food markedly increases product bioavailability.
  • Peak levels and area under curve (drug exposure) are increased (82% and 68% respectively) when product is taken with a lipid-rich meal.
  • Take with food or soon after a meal.

Targets

1. Extracellular calcium-sensing receptor

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: agonist

Components

Name UniProt ID Details
Extracellular calcium-sensing receptor P41180 Details

References:

  1. de Francisco AL: Cinacalcet HCl: a novel therapeutic for hyperparathyroidism. Expert Opin Pharmacother. 2005 Mar;6(3):441-52. Pubmed
  2. Rothe HM, Shapiro WB, Sun WY, Chou SY: Calcium-sensing receptor gene polymorphism Arg990Gly and its possible effect on response to cinacalcet HCl. Pharmacogenet Genomics. 2005 Jan;15(1):29-34. Pubmed
  3. Tasic V: Management of renal osteodystrophy in children. Turk J Pediatr. 2005;47 Suppl:13-8. Pubmed
  4. Moe SM, Cunningham J, Bommer J, Adler S, Rosansky SJ, Urena-Torres P, Albizem MB, Guo MD, Zani VJ, Goodman WG, Sprague SM: Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl. Nephrol Dial Transplant. 2005 Oct;20(10):2186-93. Epub 2005 Jul 19. Pubmed
  5. Cunningham J: Management of secondary hyperparathyroidism. Ther Apher Dial. 2005 Aug;9 Suppl 1:S35-40. Pubmed
  6. Eriguchi R, Umakoshi J, Tominaga Y, Sato Y: Successful treatment of inoperable recurrent secondary hyperparathyroidism with cinacalcet HCl. NDT Plus. 2008 Aug;1(4):218-220. Epub 2008 May 25. Pubmed
  7. Belozeroff V, Goodman WG, Ren L, Kalantar-Zadeh K: Cinacalcet lowers serum alkaline phosphatase in maintenance hemodialysis patients. Clin J Am Soc Nephrol. 2009 Mar;4(3):673-9. Epub 2009 Mar 4. Pubmed
  8. Meola M, Petrucci I, Barsotti G: Long-term treatment with cinacalcet and conventional therapy reduces parathyroid hyperplasia in severe secondary hyperparathyroidism. Nephrol Dial Transplant. 2009 Mar;24(3):982-9. Epub 2009 Jan 30. Pubmed
  9. Drueke TB, Ritz E: Treatment of secondary hyperparathyroidism in CKD patients with cinacalcet and/or vitamin D derivatives. Clin J Am Soc Nephrol. 2009 Jan;4(1):234-41. Epub 2008 Dec 3. Pubmed
  10. 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 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Padhi D, Harris R: Clinical pharmacokinetic and pharmacodynamic profile of cinacalcet hydrochloride. Clin Pharmacokinet. 2009;48(5):303-11. Pubmed
  2. Dong BJ: Cinacalcet: An oral calcimimetic agent for the management of hyperparathyroidism. Clin Ther. 2005 Nov;27(11):1725-51. Pubmed

2. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

References:

  1. Padhi D, Harris R: Clinical pharmacokinetic and pharmacodynamic profile of cinacalcet hydrochloride. Clin Pharmacokinet. 2009;48(5):303-11. Pubmed
  2. Dong BJ: Cinacalcet: An oral calcimimetic agent for the management of hyperparathyroidism. Clin Ther. 2005 Nov;27(11):1725-51. Pubmed
  3. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

3. Cytochrome P450 1A2

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 1A2 P05177 Details

References:

  1. Padhi D, Harris R: Clinical pharmacokinetic and pharmacodynamic profile of cinacalcet hydrochloride. Clin Pharmacokinet. 2009;48(5):303-11. Pubmed
  2. Dong BJ: Cinacalcet: An oral calcimimetic agent for the management of hyperparathyroidism. Clin Ther. 2005 Nov;27(11):1725-51. Pubmed

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