DT-Web

DB00282 - Pamidronate


Identification
Name Pamidronate
Accession Number DB00282 (APRD01161)
Type small molecule
Description Pamidronic acid (INN) or pamidronate disodium (USAN), marketed as pamidronate disodium pentahydrate under the brand name Aredia, is a bisphosphonate. [Wikipedia]
Structure
MOL SDF PDB SMILES InChI
Categories (*)
Molecular Weight 235.0695
Groups approved
Monoisotopic Weight 235.001074735
Pharmacology
Indication For the treatment of moderate or severe hypercalcemia associated with malignancy
Mechanism of action 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.
Absorption Plasma concentration rises rapidly upon IV administration.
Protein binding Approximately 54% to human serum proteins.
Biotransformation 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.
Toxicity Side effects include an allergic reaction, kidney problems, seizures, low levels of calcium, magnesium, or phosphorus in the blood
Affected organisms
  • Humans and other mammals
Interactions
Drug Interactions Not Available
Food Interactions Not Available

Targets


Farnesyl pyrophosphate synthetase
Name Farnesyl pyrophosphate synthetase
Gene Name FDPS
Pharmacological action yes
Actions inhibitor
References
  • Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. - Pubmed
  • Bergstrom JD, Bostedor RG, Masarachia PJ, Reszka AA, Rodan G: Alendronate is a specific, nanomolar inhibitor of farnesyl diphosphate synthase. Arch Biochem Biophys. 2000 Jan 1;373(1):231-41. - Pubmed
  • Dunford JE, Thompson K, Coxon FP, Luckman SP, Hahn FM, Poulter CD, Ebetino FH, Rogers MJ: Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther. 2001 Feb;296(2):235-42. - Pubmed
  • Notarnicola M, Messa C, Cavallini A, Bifulco M, Tecce MF, Eletto D, Di Leo A, Montemurro S, Laezza C, Caruso MG: Higher farnesyl diphosphate synthase activity in human colorectal cancer inhibition of cellular apoptosis. Oncology. 2004;67(5-6):351-8. - Pubmed
  • Riebeling C, Forsea AM, Raisova M, Orfanos CE, Geilen CC: The bisphosphonate pamidronate induces apoptosis in human melanoma cells in vitro. Br J Cancer. 2002 Jul 29;87(3):366-71. - Pubmed
  • Zhang PL, Lun M, Siegelmann-Danieli N, Blasick TM, Brown RE: Pamidronate resistance and associated low ras levels in breast cancer cells: a role for combinatorial therapy. Ann Clin Lab Sci. 2004 Summer;34(3):263-70. - Pubmed
DTHybrid score 0.6228
Hydroxyapatite
Name Hydroxyapatite
Gene Name Not Available
Pharmacological action yes
Actions antagonist
References
  • Jahnke W, Henry C: An in vitro assay to measure targeted drug delivery to bone mineral. ChemMedChem. 2010 May 3;5(5):770-6. - Pubmed
DTHybrid score Not Available

Predictions


Id Partner name Gene Name Score
6058 Geranylgeranyl pyrophosphate synthetase GGPS1 0.1179
6548 4-hydroxy-3-methylbut-2-enyl diphosphate reductase ispH 0.097
6547 Isopentenyl-diphosphate Delta-isomerase 1 IDI1 0.0696
6647 Geranyltranstransferase (Farnesyldiphosphate synthase) ispA 0.0522
6596 Short-chain Z-isoprenyl diphosphate synthetase Rv1086 0.0423
5744 Undecaprenyl pyrophosphate synthetase uppS 0.0421
2756 Geranyltranstransferase ispA 0.042
6056 Receptor-type tyrosine-protein phosphatase epsilon PTPRE 0.0369
1376 Tyrosine-protein phosphatase non-receptor type 4 PTPN4 0.0369
6576 Geranylgeranyl transferase type-2 subunit beta RABGGTB 0.0365
6575 Geranylgeranyl transferase type-2 subunit alpha RABGGTA 0.0365
290 Prostaglandin G/H synthase 2 PTGS2 0.0349
4284 Pentaerythritol tetranitrate reductase onr 0.0348
6055 Receptor-type tyrosine-protein phosphatase S PTPRS 0.0322
4128 Protein farnesyltransferase subunit beta FNTB 0.0305
6057 V-type proton ATPase catalytic subunit A ATP6V1A 0.0301
4129 Protein farnesyltransferase/geranylgeranyltransferase type I alpha subunit FNTA 0.0299
3188 IspD/ispF bifunctional enzyme [Includes: 2-C-methyl-D-erythritol 4- phosphate cytidylyltransferase ispDF 0.0259
862 Multidrug resistance-associated protein 1 ABCC1 0.024
1994 Geranylgeranyl transferase type-1 subunit beta PGGT1B 0.0237
6540 Prenyltransferase Not Available 0.0224
2383 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase ispF 0.0208
2937 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase ispF 0.0208
4620 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase ispF 0.0208
6594 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase ispF 0.0208
6609 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase ispF 0.0208
6646 2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase ispF 0.0208
6595 Lantibiotic nisin-Z nisZ 0.0189
6574 GTPase KRas KRAS 0.0151
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