Identification

Name
Parathyroid hormone
Accession Number
DB05829
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Hormones
Description

Parathyroid hormone (PTH) is a single-chain polypeptide composed of 84 amino acids. As Preotact, it contains recombinant human parathyroid hormone which is identical to the full-length native 84-amino acid polypeptide. It is produced as a fusion protein. Post-translational processing involves the cleavage of the OmpA leader sequence, leaving the mature protein as a single-chain 84 amino-acids polypeptide (9.4 kDa) whose sequence is identical to that of the full-length native endogenous human PTH. It has no disulfide bonds and no glycosylation sites.

Preotact is used in the treatment of osteoporosis in postmenopausal women at high risk of osteoporotic fractures. Preotact is marketed in Europe by Nycomed. Preos is a registered trade mark owned by NPS Pharmaceuticals, Inc. The name Preos and the New Drug Application is pending approval by the U.S. Food and Drug Administration (FDA).

Protein structure
Db05829
Protein chemical formula
C408H674N126O126S2
Protein average weight
9420.0 Da
Sequences
>Parathyroid hormone
SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFVALGAPLAPRDAGSQRPRKKEDNVLV
ESHEKSLGEADKADVNVLTKAKSQ
Download FASTA Format
Synonyms
  • hPTH
  • hPTH(1-84)
  • Parathormone
  • Parathormone (human recombinant)
  • Parathyrin
  • Parathyroid hormone
  • parathyroid hormone (1-84) human recombinant
  • parathyroid hormone (rDNA)
  • Preotact
  • PTH
  • PTH(1-84)
  • rhPTH
  • rhPTH(1-84)
  • rPTH
  • rPTH(1-84)
External IDs
ALX-111 / ALX1-11 / NPSP-558 / NPSP558
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
NATPARA (parathyroid hormone)Injection, powder, lyophilized, for solution75 ug/0.08mLSubcutaneousShire-NPS Pharmaceuticals, Inc.2015-01-23Not applicableUs
NATPARA (parathyroid hormone)Injection, powder, lyophilized, for solution25 ug/0.08mLSubcutaneousShire-NPS Pharmaceuticals, Inc.2015-01-23Not applicableUs
NATPARA (parathyroid hormone)Injection, powder, lyophilized, for solution100 ug/0.08mLSubcutaneousShire-NPS Pharmaceuticals, Inc.2015-01-23Not applicableUs
NATPARA (parathyroid hormone)Injection, powder, lyophilized, for solution50 ug/0.08mLSubcutaneousShire-NPS Pharmaceuticals, Inc.2015-01-23Not applicableUs
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
PreotactParathyroid hormone (100 µg)Injection, powder, for solutionSubcutaneousNps Pharma Holdings Limited2006-04-242014-07-11Eu
International/Other Brands
Preos (NPS Pharmaceuticals, Inc.)
Categories
UNII
N19A0T0E5J
CAS number
9002-64-6

Pharmacology

Indication

For use/treatment in osteoporosis.

Associated Conditions
Pharmacodynamics

Parathyroid hormone is responsible for the fine regulation of serum calcium concentration on a minute-to-minute basis. This is achieved by the acute effects of the hormone on calcium resorption in bone and calcium reabsorption in the kidney. The phosphate mobilized from bone is excreted into the urine by means of the hormone's influence on renal phosphate handling. Parathyroid hormone also stimulates calcium absorption in the intestine, this being mediated indirectly by 1,25-dihydroxyvitamin D. Thus, a hypocalcemic stimulus of parathyroid hormone secretion results in an increased influx of calcium from three sources (bone, kidney, and intestine), resulting in a normalization of the serum calcium concentration without change in the serum phosphate concentration.

Mechanism of action

The biological actions of rhPTH are mediated through binding to at least two distinct high- affinity cell-surface receptors specific for the N-terminal and C-terminal regions of the molecule, both of which are required for normal bone metabolism. The N-terminal portion of the molecule is primarily responsible for the bone building effects of parathyroid hormone. The C-terminal portion of the molecule has antiresorptive activity and is necessary for normal regulation of N-terminal fragment activity.

TargetActionsOrganism
UParathyroid hormone/parathyroid hormone-related peptide receptor
activator
Humans
AParathyroid hormone 2 receptor
activator
Humans
Absorption

The absolute bioavailability of 100 micrograms of Preotact after subcutaneous administration in the abdomen is 55%.

Volume of distribution

The volume of distribution at steady-state following intravenous administration is approximately 5.4 liters. Intersubject variability is about 40%.

Protein binding
Not Available
Metabolism

PTH is metabolised in the liver and to a lesser extent in the kidney.

Parathyroid hormone is efficiently removed from the blood by a receptor-mediated process in the liver and is broken down into smaller peptide fragments. The fragments derived from the amino-terminus are further degraded within the cell while the fragments derived from the carboxy-terminus are released back into the blood and cleared by the kidney. These carboxy-terminal fragments are thought to play a role in the regulation of PTH activity. Under normal physiological conditions full-length PTH constitutes only 5-30% of the circulating forms of the molecule, while 70-95% is present as carboxy-terminal fragments. Following administration of Preotact, carboxy-terminal fragments make up about 60-90% of the circulating forms of the molecule. Intersubject variability in systemic clearance is about 15%.

Route of elimination

Not excreted from the body in its intact form. Circulating carboxy-terminal fragments are filtered by the kidney, but are subsequently broken down into even smaller fragments during tubular reuptake.

Half life

The mean half-life is approximately 1.5 hours.

Clearance

PTH is rapidly cleared from plasma, primarily by Kupffer cells in the liver. To a lesser extent, PTH is cleared by filtration and reabsorption by the kidney.

Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinParathyroid hormone may increase the anticoagulant activities of (R)-warfarin.
(S)-WarfarinParathyroid hormone may increase the anticoagulant activities of (S)-Warfarin.
3-isobutyl-1-methyl-7H-xanthineThe serum concentration of 3-isobutyl-1-methyl-7H-xanthine can be increased when it is combined with Parathyroid hormone.
4-hydroxycoumarinParathyroid hormone may increase the anticoagulant activities of 4-hydroxycoumarin.
6-O-benzylguanineThe serum concentration of 6-O-benzylguanine can be increased when it is combined with Parathyroid hormone.
7-DeazaguanineThe serum concentration of 7-Deazaguanine can be increased when it is combined with Parathyroid hormone.
7,9-DimethylguanineThe serum concentration of 7,9-Dimethylguanine can be increased when it is combined with Parathyroid hormone.
8-azaguanineThe serum concentration of 8-azaguanine can be increased when it is combined with Parathyroid hormone.
8-chlorotheophyllineThe serum concentration of 8-chlorotheophylline can be increased when it is combined with Parathyroid hormone.
9-DeazaguanineThe serum concentration of 9-Deazaguanine can be increased when it is combined with Parathyroid hormone.
Food Interactions
Not Available

References

Synthesis Reference

Robert L. Colescott, Geoffrey W. Tregear, "Synthesis of peptides with parathyroid hormone activity." U.S. Patent US4105602, issued May, 1977.

US4105602
General References
  1. Sosa Henriquez M, Diez Perez A: [Parathyroid hormone in the treatment of osteoporosis]. An Med Interna. 2007 Feb;24(2):87-97. [PubMed:17590097]
External Links
UniProt
P01270
KEGG Compound
C16051
PubChem Substance
347910255
Wikipedia
Preotact
ATC Codes
H05AA03 — Parathyroid hormone

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0CompletedNot AvailableBone Diseases, Endocrine / Hyperparathyroidism / Osteoporosis1
1CompletedTreatmentOsteoporosis1
1CompletedTreatmentPostmenopausal Osteoporosis (PMO)1
1CompletedTreatmentParathyroid deficiency1
1RecruitingTreatmentParathyroid deficiency1
1TerminatedTreatmentOsteopetrosis1
1WithdrawnNot AvailableBone Diseases, Endocrine / Hypercalcemia of Malignancy / Hyperparathyroidism / Osteoporosis1
2Active Not RecruitingTreatmentOsteogenesis Imperfecta1
2Active Not RecruitingTreatmentParathyroid deficiency1
2CompletedTreatmentOsteoporosis7
2CompletedTreatmentPostmenopausal Osteoporosis (PMO)1
2CompletedTreatmentParathyroid deficiency1
2TerminatedPreventionAgnogenic Myeloid Metaplasia / Aplastic Anaemia (AA) / Chronic Lymphocytic Leukaemia (CLL) / Chronic Myeloid Leukemia (CML) / Hodgkins Disease (HD) / Leukemia, Lymphocytic, Acute / Leukemia, Myelocytic, Acute / Malignant Lymphomas1
2TerminatedTreatmentHypocalcemia1
2WithdrawnTreatmentShoulder Fractures / Trochanteric Fractures1
2, 3CompletedTreatmentOsteoporosis1
2, 3CompletedTreatmentParathyroid deficiency1
3Active Not RecruitingDiagnosticParathyroid deficiency1
3Active Not RecruitingTreatmentParathyroid deficiency1
3CompletedPreventionDisruption or Dehiscence of Closure of Sternum or Sternotomy1
3CompletedTreatmentOsteoporosis6
3CompletedTreatmentParathyroid deficiency4
3RecruitingTreatmentParathyroid deficiency1
3TerminatedTreatmentDiGeorge's syndrome / Parathyroid deficiency1
4Active Not RecruitingTreatmentChronic Hypoparathyroidism / Parathyroid deficiency1
4CompletedTreatmentOsteoporosis2
4CompletedTreatmentPostmenopausal Women With Primary Osteoporosis1
4RecruitingTreatmentParathyroid deficiency1
4TerminatedTreatmentBack Pain1
4Unknown StatusTreatmentShoulder Fractures1
Not AvailableActive Not RecruitingTreatmentOsteoporosis1
Not AvailableCompletedNot AvailableClinical Use of PTH(1-84)1
Not AvailableCompletedDiagnosticControlled / Healthy Volunteers1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, powder, lyophilized, for solutionSubcutaneous100 ug/0.08mL
Injection, powder, lyophilized, for solutionSubcutaneous25 ug/0.08mL
Injection, powder, lyophilized, for solutionSubcutaneous50 ug/0.08mL
Injection, powder, lyophilized, for solutionSubcutaneous75 ug/0.08mL
Injection, powder, for solutionSubcutaneous100 µg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Activator
General Function
Protein self-association
Specific Function
This is a receptor for parathyroid hormone and for parathyroid hormone-related peptide. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and also a phosphatid...
Gene Name
PTH1R
Uniprot ID
Q03431
Uniprot Name
Parathyroid hormone/parathyroid hormone-related peptide receptor
Molecular Weight
66359.98 Da
References
  1. Jin L, Briggs SL, Chandrasekhar S, Chirgadze NY, Clawson DK, Schevitz RW, Smiley DL, Tashjian AH, Zhang F: Crystal structure of human parathyroid hormone 1-34 at 0.9-A resolution. J Biol Chem. 2000 Sep 1;275(35):27238-44. [PubMed:10837469]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Activator
General Function
Parathyroid hormone receptor activity
Specific Function
This is a specific receptor for parathyroid hormone. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. PTH2R may be responsible for PTH effects in a number of...
Gene Name
PTH2R
Uniprot ID
P49190
Uniprot Name
Parathyroid hormone 2 receptor
Molecular Weight
62235.335 Da
References
  1. Jin L, Briggs SL, Chandrasekhar S, Chirgadze NY, Clawson DK, Schevitz RW, Smiley DL, Tashjian AH, Zhang F: Crystal structure of human parathyroid hormone 1-34 at 0.9-A resolution. J Biol Chem. 2000 Sep 1;275(35):27238-44. [PubMed:10837469]

Drug created on November 18, 2007 11:28 / Updated on November 02, 2018 06:12