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(3-Amino-1-hydroxypropyliden)bisphosphonsure

Pamidronic Acid

HCID 4674
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Grundinformationen

CAS
40391-99-9
Standard-SMILES
NCCC(O)(P(=O)(O)O)P(=O)(O)O
InChIKey
WRUUGTRCQOWXEG-UHFFFAOYSA-N
Summenformel
C3H11NO7P2
Durchschnittliche Molmasse
235,07 g/mol
Monoisotopische Masse
235,00107495

Überblick

Pamidronate is a phosphonoacetic acid.

Namen und Bezeichner

Bevorzugter Name
Pamidronic Acid
IUPAC
(3-amino-1-hydroxy-1-phosphonopropyl)phosphonic acid
Lokaler Name
(3-Amino-1-hydroxypropyliden)bisphosphonsure
Englischer Name
Pamidronic acid
Summenformel
C3H11NO7P2
Molmasse
235.07

Namen und Synonyme

PAMIDRONIC ACIDpamidronate40391-99-9AmidronateAcide pamidronique(3-amino-1-hydroxy-1-phosphonopropyl)phosphonic acidAcido pamidronicoAcidum pamidronicumRibodroat(3-Amino-1-hydroxypropylidene)bisphosphonic acidDTXSID4023414AHPrBP
Weitere Namen anzeigen
(3-Amino-1-hydroxypropane-1,1-diyl)bis(phosphonic acid)DLVPanolinRescriptorPamidronicaciIflab-bb F1977-0047Delavirdine mesylate
OYY3447OMC(3-Amino-1-hydroxypropylidene)diphosphonic acidDTXCID003414(3-amino-1-hydroxypropylidene)-1,1-biphosphonateaminopropanehydroxydiphosphonateamino-1-hydroxypropane-1,1-diphosphonateRefChem:57113M05BA03

Datenbank-Bezeichner

CAS
40391-99-9
PubChem CID
4674
DTXSID
DTXSID4023414

Eigenschaften

Berechnete StruktureigenschaftenWird ergänzt

XLogP
-6,9
Polarare Oberfläche (TPSA)
161 Ų
H-Brücken-Donoren
6
H-Brücken-Akzeptoren
8
Frei drehbare Bindungen
4
Schwere Atome
13
Formalladung
0
Komplexität
243

Experimentelle und physikochemische Eigenschaften

Drugs · 2 Einträge

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

LogP-4.7
Solubility1.58e+01 g/L
Human DrugsBreast Feeding; Lactation; Milk, Human; Bisphosphonates; Bone Density Conservation Agents; Diphosphonates
Melting Point254-262
Physical DescriptionSolid

Physikochemische Eigenschaften

Schmelzpunkt
226 · 226-228°C
Siedepunkt
658.7 · 658.7±65.0 °C(Predicted)
Dichte
1.998 · 1.998±0.06 g/cm3(Predicted)
storage temp.
2 · under inert gas (nitrogen or Argon) at 2–8 °C
Löslichkeit
Methanol (Very Slightly, Heated, Sonicated), Water (Slightly, Heated, Sonicated)

Sicherheit und Regulatorisches

Sicherheitsangaben dienen nur zur Orientierung und ersetzen weder das Sicherheitsdatenblatt (SDB) des Lieferanten noch geltende Vorschriften oder eine fachliche Bewertung.

GHS-Klassifizierung

GHS Classification · 4 Einträge

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P264, P270, P301+P317, P330, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 24 reports by companies from 4 notifications to the ECHA C&L Inventory.

Gefahrenhinweise

Hazard Classes and CategoriesAcute Tox. 4 (100%)

Toxikologische Informationen

TreatmentIf overdosage occurs, symptomatic hypocalcemia could also result; such patients should be treated with short-term intravenous calcium. (L1712)
Health EffectsRare cases of uveitis, iritis, scleritis, and episcleritis have been reported, including one case of scleritis, and one case of uveitis upon separate rechallenges.
Adverse EffectsPamidronate correlates with numerous adverse effects, including hypocalcemia and resulting secondary hyperparathyroidism, acute phase response, musculoskeletal pain, various ocular events, and osteonecrosis of the jaw.
Exposure RoutesParenteral (intravenous). Plasma concentration rises rapidly upon IV administration.
Toxicity Summary · 2 Einträge

A small number of cases describe symptomatic hypocalcemia following pamidronate administration. In each case, however, patients had pre-existing derangements contributing to their symptoms, including renal insufficiency and low vitamin D levels secondary to lifestyle, previous GI surgery, and medication history. Recommendations for the management of pamidronate overdose include appropriate correction of the electrolyte disturbance and pre-treatment supplementation with calcium and Vitamin D.

Chemie und Industrie

Pharmakologische Informationen

ATC Code · 3 Einträge

M05BA03

M - Musculo-skeletal system

QM - Musculo-skeletal system

Protein BindingPamidronate is approximately 54% protein bound in serum.
Pharmacodynamics · 1 Eintrag

Pamidronic acid is a second generation, nitrogen containing bisphosphonate that inhibits osteoclast mediated bone loss It has a wide therapeutic index and a long duration of action as it can be given every 3-4 weeks for certain indications. Patients should be counselled regarding the risk of elevated blood urea nitrogen, renal tubular necrosis, and nephrotoxicity.

Mechanism of Action · 1 Eintrag

Bisphosphonates are taken into the bone where they bind to hydroxyapatite. Bone resorption by osteoclasts causes local acidification, releasing the bisphosphonate, which is taken into the osteoclast by fluid-phase endocytosis. Endocytic vesicles become acidified, releasing bisphosphonates into the cytosol of osteoclasts where they act. Osteoclasts mediate resorption of bone. When osteoclasts bind to bone they form podosomes, ring structures of F-actin. Disruption of the podosomes causes osteoclasts to detach from bones, preventing bone resorption. Nitrogen containing bisphosphonates such as pamidronate are known to induce apoptosis of hematopoietic tumor cells by inhibiting the components of the mevalonate pathway farnesyl diphosphate synthase, farnesyl diphosphate, and geranylgeranyl diphosphate. These components are essential for post-translational prenylation of GTP-binding proteins like Rap1. The lack of prenylation of these proteins interferes with their function, and in the case of Rap1, leads to apoptosis. pamidronate also activated caspases 3 and 9 which further contribute to apoptosis.

Biological Half-LifeThe mean elimination half life of pamidronate is 28±7 hours.
Metabolism/Metabolites · 2 Einträge

Pamidronate is not metabolized _in vivo_.

Pamidronate is not metabolized and is exclusively eliminated by renal excretion. Route of Elimination: Pamidronate is not metabolized and is exclusively eliminated by renal excretion. Half Life: The mean ± SD elimination half-life is 28 ± 7 hours

Zugehörige Reaktionen

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HRID 49739als Eduktuspto-grants-2004_03
Reaktionsgleichung von HRID 74141
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HRID 412673als Produktuspto-grants-2003_05
Reaktionsgleichung von HRID 980773
HRID 980773als Eduktuspto-grants-1987_01
Reaktionsgleichung von HRID 980774
HRID 980774als Eduktuspto-grants-1987_01
Reaktionsgleichung von HRID 980775
HRID 980775als Eduktuspto-grants-1987_01
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HRID 980776als Eduktuspto-grants-1987_01
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HRID 980777als Eduktuspto-grants-1987_01
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Weitere Aktionen
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ChEMBL
CHEMBL834
ChEBI
CHEBI:7903
UNII
OYY3447OMC
EC Number
254-905-2
Nikkaji
J221.669H
pka
1.44 · 1.44±0.10(Predicted)
Aggregatzustand
Solid
Farbe
Light Brown to Beige
Stabilität
Hygroscopic
InChI
InChI=1S/C3H11NO7P2/c4-2-1-3(5,12(6,7)8)13(9,10)11/h5H,1-2,4H2,(H2,6,7,8)(H2,9,10,11)
InChIKey
WRUUGTRCQOWXEG-UHFFFAOYSA-N
SMILES
C(P(=O)(O)O)(P(=O)(O)O)(O)CCN

The mechanism of action of pamidronate is inhibition of bone resorption. Pamidronate adsorbs to calcium phosphate (hydroxyapatite) crystals in bone and may directly block dissolution of this mineral component of bone. In vitro studies also suggest that inhibition of osteoclast activity contributes to inhibition of bone resorption. Pamidronate also targets farnesyl pyrophosphate (FPP) synthase. Nitrogen-containing bisphosphonates (such as pamidronate, alendronate, risedronate, ibandronate and zoledronate) appear to act as analogues of isoprenoid diphosphate lipids, thereby inhibiting FPP synthase, an enzyme in the mevalonate pathway. Inhibition of this enzyme in osteoclasts prevents the biosynthesis of isoprenoid lipids (FPP and GGPP) that are essential for the post-translational farnesylation and geranylgeranylation of small GTPase signalling proteins. This activity inhibits osteoclast activity and reduces bone resorption and turnover. In postmenopausal women, it reduces the elevated rate of bone turnover, leading to, on average, a net gain in bone mass.

Signs and SymptomsSide effects include an allergic reaction, kidney problems, seizures, low levels of calcium, magnesium, or phosphorus in the blood
Carcinogen ClassificationNo indication of carcinogenicity to humans (not listed by IARC).
Drug Induced Liver Injury · 5 Einträge

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

pamidronate

DILI Negative

Intravenous

DOI:10.1016/j.drudis.2019.09.022

Effects During Pregnancy and Lactation◉ Summary of Use during Lactation

Sicherheitsdaten

hs_code
9999999999
FDA Pharmacological Classification · 5 Einträge

OYY3447OMC

PAMIDRONIC ACID

Established Pharmacologic Class [EPC] - Bisphosphonate

Chemical Structure [CS] - Diphosphonates

Pamidronic acid is a Bisphosphonate.

MeSH Pharmacological ClassificationAgents that inhibit BONE RESORPTION and/or favor BONE MINERALIZATION and BONE REGENERATION. They are used to heal BONE FRACTURES and to treat METABOLIC BONE DISEASES such as OSTEOPOROSIS.
Absorption, Distribution and Excretion · 3 Einträge

In patients with a creatinine clearance >90mL/min, a 90mg intravenous dose reached a Cmax of 1.92±1.08µg/mL, with a Tmax of 4h, and an AUC of 10.2±6.95µg\*h/mL. In patients with a creatinine clearance 61-90mL/min, a 90mg intravenous dose reached a Cmax of 1.86±0.50µg/mL, with a Tmax of 4h, and an AUC of 10.7—3.91µg\*h/mL.[A203264 In patients with a creatinine clearance 30-60mL/min, a 90mg intravenous dose reached a Cmax of 1.84±0.58µg/mL, with a Tmax of 4h, and an AUC of 10.1±3.38µg\*h/mL. In patients with a creatinine clearance <30mL/min, a 90mg intravenous dose reached a Cmax of 1.93±0.53µg/mL, with a Tmax of 4h, and an AUC of 34.0±8.37µg\*h/mL.

Pamidronate is exclusively eliminated in the urine. By 120 hours after administration, 46±16% of the dose has been eliminated in the urine.

The mean total clearance of pamidronate is 107±50mL/min and the mean renal clearance is 49±28mL/min.

Cellular LocationsCytoplasm
Metabolite PathwaysPamidronate Action Pathway

Verwendung und Herstellung

Uses · 2 Einträge

Use (kg; approx.) in Germany (2009): >10

Pamidronate is in a class of drugs called bisphosphonates. Pamidronate reduces breakdown of the bones. Pamidronate is used in the treatment of Paget's disease of bone; to reduce high levels of calcium in the blood associated with malignancy (cancer); and to reduce the breakdown of bone due to metastases of breast cancer or multiple myeloma. For the treatment of moderate or severe hypercalcemia associated with malignancy

Anwendungen

Verwendenanticancer

Vor- und nachgelagerte Produkte

Vorgelagerte Rohstoffe

β-AlaninPhosphorige Säure-trichloridDisodium pamidronateActivated carbon,decolorNatriumhydroxidMannitol