Details of the Drug

General Information of Drug (ID: DMB4AVP)

• Drug Name: Pamidronate
• Synonyms: AHPrBP; Amidronate; Aminomux; Aminopropanehydroxydiphosphonate; Aredia; Ribodroat; Acide pamidronique; Acido pamidronico; Acidum pamidronicum; Aminohydroxypropylidene diphosphonate; Novartis brand of pamidronate disodium salt; PAMIDRONATE DISODIUM; PAMIDRONIC ACID; Pamidronate calcium; Pamidronate monosodium; Bisphosphonate 6; Acide pamidronique [INN-French]; Acido pamidronico [INN-Spanish]; Acidum pamidronicum [INN-Latin]; Pamidronic acid (INN); Pamidronic acid [INN:BAN]; Ribodroat (TN); Amino-1-hydroxypropane-1,1-diphosphonate; (3-AMINO-1-HYDROXY-1-PHOSPHONO-PROPYL)PHOSPHONIC ACID; (3-Amino-1-hydroxypropylidene)bisphosphonic acid; (3-Amino-1-hydroxypropylidene)diphosphonic acid; (3-amino-1-hydroxy-1-phosphonopropyl)phosphonic acid; (3-amino-1-hydroxypropane-1,1-diyl)bis(phosphonic acid); (3-amino-1-hydroxypropylidene)-1,1-biphosphonate; (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate; 1-hydroxy-3-aminopropane-1,1-diphosphonic acid; 3-Amino-1-hydroxypropylidene-1,1-diphosphonate

Indication

Disease Entry	ICD 11	Status	REF
Bone Paget disease	N.A.	Approved	[1]
Hypercalcaemia	5B91.0	Approved	[2]

• Therapeutic Class: Antiinflammatory Agents
• Affected Organisms: Humans and other mammals
• ATC Code:
  M05BA03: Pamidronate
  M05BA: Bisphosphonates
  M05B: DRUGS AFFECTING BONE STRUCTURE AND MINERALIZATION
  M05: DRUGS FOR TREATMENT OF BONE DISEASES
  M: MUSCULO-SKELETAL SYSTEM
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 2:
  Molecular Weight (mw); 235.07
  Logarithm of the Partition Coefficient (xlogp); -6.9
  Rotatable Bond Count (rotbonds); 4
  Hydrogen Bond Donor Count (hbonddonor); 6
  Hydrogen Bond Acceptor Count (hbondacc); 8
• ADMET Property:
  Absorption AUC: The area under the plot of plasma concentration (AUC) of drug is 10.2 +/- 6.95 mgh/L [3]
  Absorption Cmax: The maximum plasma concentration (Cmax) of drug is 1.92 +/- 1.08mg/L [3]
  Absorption Tmax: The time to maximum plasma concentration (Tmax) is 4 h [3]
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3: high solubility and low permeability [4]
  Clearance: The renal clearance of drug is 49 +/- 28 mL/min [5]
  Elimination: Pamidronate is exclusively eliminated in the urine, 46 +/- 16% of the dose has been eliminated in the urine [5]
  Half-life: The concentration or amount of drug in body reduced by one-half in 28 +/- 7 hours [5]
  Metabolism: The drug is not metabolised [5]
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 5.47 micromolar/kg/day [6]
  Unbound Fraction: The unbound fraction of drug in plasma is 0.7% [7]
  Vd: Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma 1.8 L/kg [7]
• Chemical Identifiers:
  Formula: C3H11NO7P2
  IUPAC Name: (3-amino-1-hydroxy-1-phosphonopropyl)phosphonic acid
  Canonical SMILES: C(CN)C(O)(P(=O)(O)O)P(=O)(O)O
  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
• Cross-matching ID:
  PubChem CID: 4674
  ChEBI ID: CHEBI:7903
  CAS Number: 40391-99-9
  UNII: OYY3447OMC
  DrugBank ID: DB00282
  TTD ID: D0BF8G
• Repurposed Drugs (RPD): Click to Jump to the Detailed RPD Information of This Drug

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Geranyltranstransferase (FDPS)	TTIKWV4	FPPS_HUMAN	Inhibitor	[8]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Alkaline phosphatase, tissue-nonspecific isozyme (ALPL)	OTG7J4BP	PPBT_HUMAN	Gene/Protein Processing	[9]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Gene/Protein Processing	[10]
Bcl-2-interacting killer (BIK)	OTTH1T3D	BIK_HUMAN	Drug Response	[11]
Beta-2-microglobulin (B2M)	OTDWN6NX	B2MG_HUMAN	Gene/Protein Processing	[9]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Gene/Protein Processing	[9]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Protein Interaction/Cellular Processes	[12]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Protein Interaction/Cellular Processes	[12]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Gene/Protein Processing	[13]
Fibroblast growth factor 23 (FGF23)	OTZT523D	FGF23_HUMAN	Gene/Protein Processing	[14]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Gene/Protein Processing	[9]

Molecular Expression Atlas of This Drug

• The Studied Disease: Bone Paget disease

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Geranyltranstransferase (FDPS)	DTT	FDPS	7.06E-03	-0.73	-2.57

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Same Disease as Pamidronate

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Disease	REF
Gallium nitrate	DMF9O6B	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Gallium nitrate.	Mineral excesses [5B91]	[15]

Coadministration of a Drug Treating the Disease Different from Pamidronate (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Remdesivir	DMBFZ6L	Moderate	Decreased renal excretion of Pamidronate caused by Remdesivir mediated nephrotoxicity.	1D6YCoronavirus Disease 2019 [1D6YCoronavirus Disease 2019]	[16]
Framycetin	DMF8DNE	Moderate	Increased risk of hypocalcemia by the combination of Pamidronate and Framycetin.	Alcoholic liver disease [DB94]	[15]
Inotersen	DMJ93CT	Major	Increased risk of nephrotoxicity by the combination of Pamidronate and Inotersen.	Amyloidosis [5D00]	[16]
Kanamycin	DM2DMPO	Moderate	Increased risk of hypocalcemia by the combination of Pamidronate and Kanamycin.	Bacterial infection [1A00-1C4Z]	[15]
Amikacin	DM5PDRB	Moderate	Increased risk of hypocalcemia by the combination of Pamidronate and Amikacin.	Bacterial infection [1A00-1C4Z]	[15]
Streptomycin	DME1LQN	Moderate	Increased risk of hypocalcemia by the combination of Pamidronate and Streptomycin.	Bacterial infection [1A00-1C4Z]	[15]
Gentamicin	DMKINJO	Moderate	Increased risk of hypocalcemia by the combination of Pamidronate and Gentamicin.	Bacterial infection [1A00-1C4Z]	[15]
Capreomycin	DMNZBRY	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Capreomycin.	Bacterial infection [1A00-1C4Z]	[15]
Netilmicin	DMRD1QK	Moderate	Increased risk of hypocalcemia by the combination of Pamidronate and Netilmicin.	Bacterial infection [1A00-1C4Z]	[15]
Tobramycin	DMUI0CH	Moderate	Increased risk of hypocalcemia by the combination of Pamidronate and Tobramycin.	Bacterial infection [1A00-1C4Z]	[15]
Iodipamide	DMXIQYS	Major	Increased risk of nephrotoxicity by the combination of Pamidronate and Iodipamide.	Cholelithiasis [DC11]	[17]
Phenylbutazone	DMAYL0T	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Phenylbutazone.	Chronic pain [MG30]	[18]
Ketoprofen	DMRKXPT	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Ketoprofen.	Chronic pain [MG30]	[18]
Oxaliplatin	DMQNWRD	Moderate	Decreased renal excretion of Pamidronate caused by Oxaliplatin mediated nephrotoxicity.	Colorectal cancer [2B91]	[19]
Methoxyflurane	DML0RAE	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Methoxyflurane.	Corneal disease [9A76-9A78]	[15]
Cidofovir	DMA13GD	Major	Increased risk of nephrotoxicity by the combination of Pamidronate and Cidofovir.	Cytomegaloviral disease [1D82]	[20]
Ethacrynic acid	DM60QMR	Moderate	Increased risk of hypocalcemia by the combination of Pamidronate and Ethacrynic acid.	Essential hypertension [BA00]	[21]
Mefenamic acid	DMK7HFI	Moderate	Increased risk of GI mucosal injury/bleeding risk by the combination of Pamidronate and Mefenamic acid.	Female pelvic pain [GA34]	[18]
Pentamidine	DMHZJCG	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Pentamidine.	Fungal infection [1F29-1F2F]	[15]
Amphotericin B	DMTAJQE	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Amphotericin B.	Fungal infection [1F29-1F2F]	[15]
Furosemide	DMMQ8ZG	Moderate	Increased risk of hypocalcemia by the combination of Pamidronate and Furosemide.	Heart failure [BD10-BD1Z]	[21]
Bumetanide	DMRV7H0	Moderate	Increased risk of hypocalcemia by the combination of Pamidronate and Bumetanide.	Heart failure [BD10-BD1Z]	[21]
177Lu-DOTATATE	DMT8GVU	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and 177Lu-DOTATATE.	Hepatitis virus infection [1E50-1E51]	[15]
Etelcalcetide	DMHP9BL	Major	Increased risk of hypocalcemia by the combination of Pamidronate and Etelcalcetide.	Hyper-parathyroidism [5A51]	[16]
Givosiran	DM5PFIJ	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Givosiran.	Inborn porphyrin/heme metabolism error [5C58]	[15]
Balsalazide	DM7I1T9	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Balsalazide.	Indeterminate colitis [DD72]	[15]
Meclofenamic acid	DM05FXR	Moderate	Increased risk of GI mucosal injury/bleeding risk by the combination of Pamidronate and Meclofenamic acid.	Inflammatory spondyloarthritis [FA92]	[18]
Methotrexate	DM2TEOL	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Methotrexate.	Leukaemia [2A60-2B33]	[15]
Moxetumomab pasudotox	DMN63DZ	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Moxetumomab pasudotox.	Mature B-cell leukaemia [2A82]	[15]
Clofarabine	DMCVJ86	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Clofarabine.	Mature B-cell lymphoma [2A85]	[22]
Exjade	DMHPRWG	Major	Increased risk of nephrotoxicity by the combination of Pamidronate and Exjade.	Mineral absorption/transport disorder [5C64]	[23]
Rofecoxib	DM3P5DA	Moderate	Increased risk of GI mucosal injury/bleeding risk by the combination of Pamidronate and Rofecoxib.	Osteoarthritis [FA00-FA05]	[18]
Valdecoxib	DMAY7H4	Moderate	Increased risk of GI mucosal injury/bleeding risk by the combination of Pamidronate and Valdecoxib.	Osteoarthritis [FA00-FA05]	[18]
Diclofenac	DMPIHLS	Moderate	Increased risk of GI mucosal injury/bleeding risk by the combination of Pamidronate and Diclofenac.	Osteoarthritis [FA00-FA05]	[18]
Naproxen	DMZ5RGV	Moderate	Increased risk of GI mucosal injury/bleeding risk by the combination of Pamidronate and Naproxen.	Osteoarthritis [FA00-FA05]	[18]
Aspirin	DM672AH	Moderate	Increased risk of GI mucosal injury/bleeding risk by the combination of Pamidronate and Aspirin.	Pain [MG30-MG3Z]	[18]
Diflunisal	DM7EN8I	Moderate	Increased risk of GI mucosal injury/bleeding risk by the combination of Pamidronate and Diflunisal.	Pain [MG30-MG3Z]	[18]
Ibuprofen	DM8VCBE	Moderate	Increased risk of GI mucosal injury/bleeding risk by the combination of Pamidronate and Ibuprofen.	Pain [MG30-MG3Z]	[18]
Nabumetone	DMAT2XH	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Nabumetone.	Pain [MG30-MG3Z]	[18]
Piroxicam	DMTK234	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Piroxicam.	Pain [MG30-MG3Z]	[18]
Pemetrexed	DMMX2E6	Moderate	Decreased renal excretion of Pamidronate caused by Pemetrexed mediated nephrotoxicity.	Pleural mesothelioma [2C26]	[24]
Choline salicylate	DM8P137	Moderate	Increased risk of GI mucosal injury/bleeding risk by the combination of Pamidronate and Choline salicylate.	Postoperative inflammation [1A00-CA43]	[18]
Ketorolac	DMI4EL5	Moderate	Increased risk of GI mucosal injury/bleeding risk by the combination of Pamidronate and Ketorolac.	Postoperative inflammation [1A00-CA43]	[18]
Bromfenac	DMKB79O	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Bromfenac.	Postoperative inflammation [1A00-CA43]	[18]
Temsirolimus	DMS104F	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Temsirolimus.	Renal cell carcinoma [2C90]	[15]
Colistimethate	DMZ9BMU	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Colistimethate.	Respiratory infection [CA07-CA4Z]	[15]
Salsalate	DM13P4C	Moderate	Increased risk of GI mucosal injury/bleeding risk by the combination of Pamidronate and Salsalate.	Rheumatoid arthritis [FA20]	[18]
Meloxicam	DM2AR7L	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Meloxicam.	Rheumatoid arthritis [FA20]	[18]
Sulindac	DM2QHZU	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Sulindac.	Rheumatoid arthritis [FA20]	[18]
Celecoxib	DM6LOQU	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Celecoxib.	Rheumatoid arthritis [FA20]	[18]
Oxaprozin	DM9UB0P	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Oxaprozin.	Rheumatoid arthritis [FA20]	[18]
Flurbiprofen	DMGN4BY	Moderate	Increased risk of GI mucosal injury/bleeding risk by the combination of Pamidronate and Flurbiprofen.	Rheumatoid arthritis [FA20]	[18]
Sulfasalazine	DMICA9H	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Sulfasalazine.	Rheumatoid arthritis [FA20]	[15]
Fenoprofen	DML5VQ0	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Fenoprofen.	Rheumatoid arthritis [FA20]	[18]
Indomethacin	DMSC4A7	Moderate	Increased risk of GI mucosal injury/bleeding risk by the combination of Pamidronate and Indomethacin.	Rheumatoid arthritis [FA20]	[18]
Tolmetin	DMWUIJE	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Tolmetin.	Rheumatoid arthritis [FA20]	[18]
Salicyclic acid	DM2F8XZ	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Salicyclic acid.	Seborrhoeic dermatitis [EA81]	[18]
Bacitracin	DM5OHYE	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Bacitracin.	Skin and skin-structure infection [1F28-1G0Z]	[15]
Cisplatin	DMRHGI9	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Cisplatin.	Solid tumour/cancer [2A00-2F9Z]	[15]
Telavancin	DM58VQX	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Telavancin.	Staphylococcal/streptococcal disease [1B5Y]	[15]
Lenvatinib	DMB1IU4	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Lenvatinib.	Thyroid cancer [2D10]	[15]
Sirolimus	DMGW1ID	Major	Increased risk of nephrotoxicity by the combination of Pamidronate and Sirolimus.	Transplant rejection [NE84]	[25]
Tacrolimus	DMZ7XNQ	Major	Increased risk of nephrotoxicity by the combination of Pamidronate and Tacrolimus.	Transplant rejection [NE84]	[25]
Olsalazine	DMZW9HA	Moderate	Increased risk of nephrotoxicity by the combination of Pamidronate and Olsalazine.	Ulcerative colitis [DD71]	[15]
Plazomicin	DMKMBES	Moderate	Increased risk of hypocalcemia by the combination of Pamidronate and Plazomicin.	Urinary tract infection [GC08]	[15]

References

• [1] Pamidronate FDA Label
• [2] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7259).
• [3] Berenson JR, Rosen L, Vescio R, Lau HS, Woo M, Sioufi A, Kowalski MO, Knight RD, Seaman JJ: Pharmacokinetics of pamidronate disodium in patients with cancer with normal or impaired renal function. J Clin Pharmacol. 1997 Apr;37(4):285-90. doi: 10.1002/j.1552-4604.1997.tb04304.x.
• [4] BDDCS applied to over 900 drugs
• [5] FDA Approved Drug Products: Aredia Pamidronate Intravenous Injection
• [6] Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
• [7] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [8] Detection of nonsterol isoprenoids by HPLC-MS/MS. Anal Biochem. 2008 Dec 1;383(1):18-24.
• [9] Pamidronate increases markers of bone formation in patients with multiple myeloma in plateau phase under interferon-alpha treatment. Calcif Tissue Int. 2001 May;68(5):285-90.
• [10] Bisphosphonates induce apoptosis in human breast cancer cell lines. Br J Cancer. 2000 Apr;82(8):1459-68. doi: 10.1054/bjoc.1999.1131.
• [11] Caspase-independent induction of apoptosis in human melanoma cells by the proapoptotic Bcl-2-related protein Nbk / Bik. Oncogene. 2005 Nov 10;24(49):7369-80. doi: 10.1038/sj.onc.1208890.
• [12] Pamidronate induced anti-proliferative, apoptotic, and anti-migratory effects in hepatocellular carcinoma. J Hepatol. 2006 Jan;44(1):142-50. doi: 10.1016/j.jhep.2005.09.022. Epub 2005 Nov 9.
• [13] Expression profile and synthesis of different collagen types I, II, III, and V of human gingival fibroblasts, osteoblasts, and SaOS-2 cells after bisphosphonate treatment. Clin Oral Investig. 2010 Feb;14(1):51-8. doi: 10.1007/s00784-009-0312-2. Epub 2009 Jul 14.
• [14] The role of fibroblast growth factor 23 for hypophosphatemia and abnormal regulation of vitamin D metabolism in patients with McCune-Albright syndrome. J Bone Miner Metab. 2005;23(3):231-7. doi: 10.1007/s00774-004-0589-9.
• [15] Chang JT, Green L, Beitz J "Renal failure with the use of zoledronic acid." N Engl J Med 349 (2003): 1676-9 discussion 1676-9. [PMID: 14573746]
• [16] Cerner Multum, Inc. "UK Summary of Product Characteristics.".
• [17] Bentley ML, Corwin HL, Dasta J "Drug-induced acute kidney injury in the critically ill adult: recognition and prevention strategies." Crit Care Med 38(6 Suppl) (2010): S169-74. [PMID: 20502171]
• [18] Product Information. Actonel (risedronate). Procter and Gamble Pharmaceuticals, Cincinnati, OH.
• [19] Product Information. Eloxatin (oxaliplatin). Sanofi Winthrop Pharmaceuticals, New York, NY.
• [20] Product Information. Vistide (cidofovir). Gilead Sciences, Foster City, CA.
• [21] Product Information. Skelid (tilundronate). Sanofi Winthrop Pharmaceuticals, New York, NY.
• [22] Product Information. Clolar (clofarabine). sanofi-aventis, Bridgewater, NJ.
• [23] Product Information. Exjade (deferasirox). Novartis Pharmaceuticals, East Hanover, NJ.
• [24] Product Information. Alimta (pemetrexed). Lilly, Eli and Company, Indianapolis, IN.
• [25] Product Information. Prograf (tacrolimus). Fujisawa, Deerfield, IL.