Identification

Name
Zoledronic acid
Accession Number
DB00399  (APRD01294, DB06286)
Type
Small Molecule
Groups
Approved
Description

Zoledronate (zoledronic acid, marketed by Novartis under the trade names Zometa and Reclast) is a bisphosphonate. Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer. It can also be used to treat hypercalcemia of malignancy and can be helpful for treating pain from bone metastases.

An annual dose of Zoledronate may also prevent recurring fractures in patients with a previous hip fracture.

Zoledronate is a single 5 mg infusion for the treatment of Paget's disease of bone. In 2007, the FDA also approved Reclast for the treatment of postmenopausal osteoporosis.

Structure
Thumb
Synonyms
  • (1-hydroxy-2-(1H-imidazol-1-yl)ethylidene)bisphosphonic acid
  • (1-hydroxy-2-imidazol-1-ylethylidene)diphosphonic acid
  • Anhydrous Zoledronic Acid
  • Zol
  • Zoledronate
  • Zoledronic Acid Anhydrous
  • Zoledronic Acid, Anhydrous
External IDs
CGP 42446 / CGP-42446
Product Ingredients
IngredientUNIICASInChI Key
Zoledronate disodium7D7GS1SA24165800-07-7IEJZOPBVBXAOBH-UHFFFAOYSA-L
Zoledronate trisodiumARL915IH66165800-08-8Not applicable
Zoledronic acid hemipentahydrate1K9U67HDIDNot AvailableAZZILOGHCMYHQY-UHFFFAOYSA-N
Zoledronic acid monohydrate6XC1PAD3KF165800-06-6FUXFIVRTGHOMSO-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AclastaInjection, solution5 mg/100mlIntravenousNovartis Europharm Limited2005-04-15Not applicableEu
AclastaInjection, solution5 mg/100mlIntravenousNovartis Europharm Limited2005-04-15Not applicableEu
AclastaSolution5 mgIntravenousNovartis2005-08-22Not applicableCanada
Act Zoledronic AcidSolution5 mgIntravenousActavis Pharma CompanyNot applicableNot applicableCanada
Act Zoledronic Acid ConcentrateSolution4 mgIntravenousActavis Pharma CompanyNot applicableNot applicableCanada
ReclastInjection, solution5 mg/100mLIntravenousNovartis2007-04-01Not applicableUs
Zoledronic AcidInjection, solution4 mg/100mLIntravenousHospira, Inc.2017-10-19Not applicableUs
Zoledronic AcidInjection, solution0.04 mg/1mLIntravenousSagent Pharmaceuticals2013-03-02Not applicableUs
Zoledronic Acid - ASolution5 mgIntravenousSandoz Canada IncorporatedNot applicableNot applicableCanada
Zoledronic Acid - ZSolution4 mgIntravenousSandoz Canada Incorporated2014-01-15Not applicableCanada
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
PMS-zoledronic AcidSolution4 mgIntravenousPharmascience Inc2014-11-25Not applicableCanada
Taro-zoledronic AcidSolution5 mgIntravenousTaro Pharmaceuticals, Inc.2014-04-02Not applicableCanada
Taro-zoledronic Acid ConcentrateSolution4 mgIntravenousTaro Pharmaceuticals, Inc.2014-02-26Not applicableCanada
Val-zoledronic AcidSolution4 mgIntravenousValeo Pharma Corp.Not applicableNot applicableCanada
Zoledronic AcidInjection, solution, concentrate4 mg/5mLIntravenousBpi Labs Llc2018-04-02Not applicableUs
Zoledronic AcidInjection, solution, concentrate4 mg/5mLIntravenousPar Pharmaceutical Companies2013-03-04Not applicableUs
Zoledronic AcidInjection, solution5 mg/100mLIntravenousGland Pharma Limited2016-09-15Not applicableUs
Zoledronic AcidInjection, solution, concentrate4 mg/5mLIntravenousJHP Pharmaceuticals, LLC.2013-05-07Not applicableUs
Zoledronic AcidInjection, solution5 mg/100mLIntravenousAuro Medics Pharma Llc2017-12-08Not applicableUs
Zoledronic AcidInjection5 mg/100mLIntravenousBreckenridge Pharmaceutical, Inc.2017-09-15Not applicableUs
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Zoledronic Acid Teva GenericsZoledronic acid monohydrate (5 mg)Injection, solutionIntravenousTeva Generics B.V2014-03-272016-08-08Eu
Zoledronic Acid Teva GenericsZoledronic acid monohydrate (5 mg)Injection, solutionIntravenousTeva Generics B.V2014-03-272016-08-08Eu
Zoledronic Acid Teva GenericsZoledronic acid monohydrate (5 mg)Injection, solutionIntravenousTeva Generics B.V2014-03-272016-08-08Eu
Zoledronic Acid Teva GenericsZoledronic acid monohydrate (5 mg)Injection, solutionIntravenousTeva Generics B.V2014-03-272016-08-08Eu
Zoledronic Acid Teva GenericsZoledronic acid monohydrate (5 mg)Injection, solutionIntravenousTeva Generics B.V2014-03-272016-08-08Eu
Categories
UNII
70HZ18PH24
CAS number
118072-93-8
Weight
Average: 272.0896
Monoisotopic: 271.996323708
Chemical Formula
C5H10N2O7P2
InChI Key
XRASPMIURGNCCH-UHFFFAOYSA-N
InChI
InChI=1S/C5H10N2O7P2/c8-5(15(9,10)11,16(12,13)14)3-7-2-1-6-4-7/h1-2,4,8H,3H2,(H2,9,10,11)(H2,12,13,14)
IUPAC Name
[1-hydroxy-2-(1H-imidazol-1-yl)-1-phosphonoethyl]phosphonic acid
SMILES
OC(CN1C=CN=C1)(P(O)(O)=O)P(O)(O)=O

Pharmacology

Indication

For the treatment of hypercalcemia of malignancy. Also for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. In May of 2007, the drug was approved for treatment of Paget’s Disease.

Associated Conditions
Pharmacodynamics

Zoledronate is a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronate is used to prevent osteoporosis and skeletal fractures, particularly in patients with cancers such as multiple myeloma and prostate cancer. It can also be used to treat hypercalcemia, particularly hypercalcemia of malignancy. It can also be helpful for treating pain from bone metastases.

Mechanism of action

The action of zoledronate on bone tissue is based partly on its affinity for hydroxyapatite, which is part of the mineral matrix of bone. Zoledronate also targets farnesyl pyrophosphate (FPP) synthase. Nitrogen-containing bisphosphonates such as 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.

TargetActionsOrganism
AFarnesyl pyrophosphate synthase
inhibitor
Human
AGeranylgeranyl pyrophosphate synthase
inhibitor
Human
AHydroxylapatite
antagonist
Human
Absorption

Poorly absorbed (oral absorption is about 1% of what intravenous absorption is).

Volume of distribution
Not Available
Protein binding

Approximately 22% bound in human plasma, independent of the concentration. However, Canadian product information states binding to human plasma protein is approximately 56%.

Metabolism

Zoledronate does not inhibit human P450 enzymes in vitro and does not undergo biotransformation in vivo.

Route of elimination

In 64 patients with cancer and bone metastases, on average (± s.d.) 39 ± 16% of the administered zoledronic acid dose was recovered in the urine within 24 hours, with only trace amounts of drug found in urine post-Day 2.

Half life

146 hours

Clearance
  • Renal cl=3.7 +/- 2.0 L/h
Toxicity

There is no experience of acute overdose. Two patients received zoledronate (32 mg) over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia.

Affected organisms
  • Humans and other mammals
Pathways
PathwayCategory
Zoledronate Action PathwayDrug action
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AceclofenacThe risk or severity of gastrointestinal bleeding can be increased when Aceclofenac is combined with Zoledronic acid.
AcemetacinThe risk or severity of gastrointestinal bleeding can be increased when Acemetacin is combined with Zoledronic acid.
Acetylsalicylic acidThe risk or severity of gastrointestinal bleeding can be increased when Acetylsalicylic acid is combined with Zoledronic acid.
Adefovir DipivoxilThe risk or severity of nephrotoxicity and hypocalcemia can be increased when Adefovir Dipivoxil is combined with Zoledronic acid.
AlclofenacThe risk or severity of gastrointestinal bleeding can be increased when Alclofenac is combined with Zoledronic acid.
Alendronic acidThe risk or severity of hypocalcemia can be increased when Zoledronic acid is combined with Alendronic acid.
AlmasilateThe serum concentration of Zoledronic acid can be decreased when it is combined with Almasilate.
AlminoprofenThe risk or severity of gastrointestinal bleeding can be increased when Alminoprofen is combined with Zoledronic acid.
AloglutamolThe serum concentration of Zoledronic acid can be decreased when it is combined with Aloglutamol.
AluminiumThe serum concentration of Zoledronic acid can be decreased when it is combined with Aluminium.
Food Interactions
Not Available

References

Synthesis Reference

Judith Aronhime, Revital Lifshitz-Liron, "Zoledronic acid crystal forms, zoledronate sodium salt crystal forms, amorphous zoledronate sodium salt, and processes for their preparation." U.S. Patent US20050054616, issued March 10, 2005.

US20050054616
General References
  1. Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S: Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007 Nov 1;357(18):1799-809. Epub 2007 Sep 17. [PubMed:17878149]
  2. Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U, Widmer A, Devogelaer JP, Kaufman JM, Jaeger P, Body JJ, Brandi ML, Broell J, Di Micco R, Genazzani AR, Felsenberg D, Happ J, Hooper MJ, Ittner J, Leb G, Mallmin H, Murray T, Ortolani S, Rubinacci A, Saaf M, Samsioe G, Verbruggen L, Meunier PJ: Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med. 2002 Feb 28;346(9):653-61. [PubMed:11870242]
  3. Durie BG, Katz M, Crowley J: Osteonecrosis of the jaw and bisphosphonates. N Engl J Med. 2005 Jul 7;353(1):99-102; discussion 99-102. [PubMed:16000365]
External Links
Human Metabolome Database
HMDB0014543
KEGG Drug
D01968
PubChem Compound
68740
PubChem Substance
46507310
ChemSpider
61986
BindingDB
12578
ChEBI
46557
ChEMBL
CHEMBL924
Therapeutic Targets Database
DAP001539
PharmGKB
PA10235
HET
ZOL
RxList
RxList Drug Page
Wikipedia
Zoledronate
ATC Codes
M05BB08 — Zoledronic acid, calcium and colecalciferol, sequentialM05BA08 — Zoledronic acid
AHFS Codes
  • 92:24.00 — Bone Resorption Inhibitors
PDB Entries
1zw5 / 2e91 / 2f8c / 2f8z / 2f9k / 2q58 / 3ez3 / 3iba / 3ldw / 3n45
show 5 more
MSDS
Download (57.9 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentNeuroblastomas1
1CompletedBasic ScienceHealthy Postmenopausal Women1
1CompletedOtherHealthy Volunteers1
1CompletedOtherRisk Factors for or a Diagnosis of Osteoporosis1
1CompletedTreatmentBone Metastases / Cancer, Breast / Lung Cancers / Prostate Cancer1
1CompletedTreatmentCLDN18.2-positive Adenocarcinoma of Esophagus / CLDN18.2-positive Adenocarcinoma of the Gastroesophageal Junction / CLDN18.2-positive Gastric Adenocarcinoma1
1CompletedTreatmentCancer, Breast / Multiple Myeloma (MM)1
1CompletedTreatmentMetastatic Hormone Refractory Prostate Cancer1
1CompletedTreatmentMultiple Myeloma Bone Disease1
1CompletedTreatmentNeuroblastomas1
1CompletedTreatmentProstate Cancer1
1CompletedTreatmentSarcomas1
1RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Ewing's Sarcoma (ES) / Leukemia Acute Myeloid Leukemia (AML) / Lymphoma, Hodgkins / Myelodysplastic Syndrome / Myeloproliferative Syndromes / Neuroblastomas / Non-Hodgkin's Lymphoma (NHL) / Primitive Neuroectodermal Tumor / Rhabdomyosarcomas / Sarcoma, Osteogenic1
1RecruitingTreatmentChondrosarcomas1
1TerminatedTreatmentAdenocarcinomas1
1TerminatedTreatmentCervical Cancers / Precancerous Conditions1
1TerminatedTreatmentMultiple Myeloma and Plasma Cell Neoplasm1
1TerminatedTreatmentNeuroblastomas1
1, 2Active Not RecruitingTreatmentBone Metastases / Cancer, Breast1
1, 2CompletedSupportive CareCancer, Breast / Hypercalcemia of Malignancy / Metastatic Cancers / Pain1
1, 2CompletedTreatmentMetastatic Cancers / Renal Cancers1
1, 2CompletedTreatmentMultiple Myeloma and Plasma Cell Neoplasm / Pain1
1, 2WithdrawnNot AvailableSickle Cell Disorders1
2Active Not RecruitingPreventionBone destruction / Bone Loss / Spinal Cord Injuries (SCI) / Spinal Cord Injury, Acute1
2Active Not RecruitingSupportive CareBone destruction / Cancer of the Ovary / Hereditary Breast and Ovarian Cancer Syndrome / Hereditary Breast/Ovarian Cancer (brca1, brca2) / Ovarian Carcinoma1
2Active Not RecruitingTreatmentOsteogenesis Imperfecta1
2Active Not RecruitingTreatmentBone destruction1
2CompletedPreventionBone Loss / Prostate Cancer1
2CompletedSupportive CareBone destruction / Central Nervous System(CNS)Malignancies / Neoplasms, Brain1
2CompletedSupportive CareDuctal Carcinoma In Situ / Estrogen Receptor-Positive Breast Cancer / Progesterone Receptor-positive Breast Cancer / Stage I Breast Carcinoma / Stage II Breast Cancer / Stage IIIA Breast Cancer / Stage IIIB Breast Cancer / Stage IIIC Breast Cancer1
2CompletedTreatmentAdenocarcinoma of the Prostate / Prostate Cancer1
2CompletedTreatmentAdenocarcinoma of the Prostate / Recurrent Prostate Cancer / Stage IV Prostate Cancer1
2CompletedTreatmentAgnogenic Myeloid Metaplasia / Myeloid Metaplasia1
2CompletedTreatmentBone destruction / Bone Loss / Human Immunodeficiency Virus (HIV) Infections / Osteopenia1
2CompletedTreatmentBone Metastasis / Gastrointestinal Cancers1
2CompletedTreatmentBone Neoplasms / Cancer, Breast / Prostate Cancer1
2CompletedTreatmentBone destruction / Cancer of the Ovary / Leukemias / Malignant Lymphomas / Myelodysplastic Syndromes1
2CompletedTreatmentCancer, Breast2
2CompletedTreatmentCancer, Breast / Metastatic Bone Disease1
2CompletedTreatmentCancer, Breast / Multiple Myeloma (MM)1
2CompletedTreatmentDuctal Histologic Type / Locally Advanced Breast Cancer (LABC) / Without Her2 Overexpression1
2CompletedTreatmentHormone-Refractory Prostate Cancer2
2CompletedTreatmentHutchinson-Gilford Syndrome / Progeria1
2CompletedTreatmentLow Back Pain (LBP)1
2CompletedTreatmentLow Bone Mineral Density / Postmenopausal Osteoporosis (PMO)1
2CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC)1
2CompletedTreatmentMalignant Neoplasm of Nasopharynx1
2CompletedTreatmentMesothelioma1
2CompletedTreatmentMetastatic Cancers / Prostate Cancer2
2CompletedTreatmentMultiple Myeloma (MM)5
2CompletedTreatmentNeoplasms, Breast1
2CompletedTreatmentOsteogenesis Imperfecta2
2CompletedTreatmentProstate Cancer1
2CompletedTreatmentRenal Cancers / Renal Cell Adenocarcinoma1
2CompletedTreatmentUrologic Neoplasms1
2Not Yet RecruitingTreatmentTriple Negative Breast Cancer (TNBC)1
2RecruitingTreatmentAdenocarcinoma of the Pancreas / Recurrent Pancreatic Carcinoma / Stage I Pancreatic Cancer / Stage IA Pancreatic Cancer / Stage IB Pancreatic Cancer / Stage II Pancreatic Cancer / Stage IIA Pancreatic Cancer / Stage IIB Pancreatic Cancer / Stage III Pancreatic Cancer / Stage IV Pancreatic Cancer1
2RecruitingTreatmentBone Metastases / Prostate Cancer1
2RecruitingTreatmentBone Metastasis / Gastrointestinal Cancers1
2RecruitingTreatmentCancer, Breast1
2RecruitingTreatmentBone destruction / IOP1
2TerminatedDiagnosticMetastases / Non-Small Cell Lung Carcinoma (NSCLC) / Small Cell Lung Carcinoma1
2TerminatedPreventionBone Loss1
2TerminatedPreventionMultiple Myeloma (MM)1
2TerminatedPreventionProstate Cancer1
2TerminatedTreatmentChronic Myeloid Leukemia (CML)1
2TerminatedTreatmentGiant Cell Tumors of Bone / Osteoclastoma1
2TerminatedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC) / Malignant Pleural Effusions1
2TerminatedTreatmentRenal Cancers1
2TerminatedTreatmentUterine Cervical Neoplasms1
2Unknown StatusPreventionOsteonecrosis1
2Unknown StatusTreatmentBreast Diseases / Cancer, Breast / Neoplasms / Neoplasms by Site1
2Unknown StatusTreatmentComplex Regional Pain Syndromes (CRPS)1
2Unknown StatusTreatmentHepatocellular,Carcinoma1
2Unknown StatusTreatmentBone destruction / Human Immunodeficiency Virus (HIV) Infections / Osteopenia1
2WithdrawnTreatmentAcute Lymphoblastic Leukaemias (ALL) / Bone destruction / Osteonecrosis1
2WithdrawnTreatmentOsteonecrosis1
2WithdrawnTreatmentPlasma Cell Myeloma1
2, 3CompletedPreventionBone Resorption / Heart Transplantation / Transplantation, Liver1
2, 3CompletedPreventionMetastatic Breast Cancer With Bone Involvement1
2, 3CompletedTreatmentBone Metastases / Metastatic Breast Cancer (MBC)1
2, 3RecruitingTreatmentDiabetes Complications / Neuropathic arthropathy1
2, 3RecruitingTreatmentProstate Cancer2
2, 3TerminatedTreatmentBone destruction1
2, 3Unknown StatusTreatmentBeta-Thalassemia / Transplantation, Bone Marrow1
2, 3Unknown StatusTreatmentCancer, Breast1
2, 3Unknown StatusTreatmentSarcoma, Osteogenic1
3Active Not RecruitingSupportive CareBone Metastases / Cancers / Malignancies, Hematologic / Multiple Myeloma (MM) / Multiple Myeloma Bone Lesions / Oncology1
3Active Not RecruitingSupportive CareBreast Adenocarcinoma / DS Stage I Plasma Cell Myeloma / DS Stage II Plasma Cell Myeloma / Metastatic Malignant Neoplasm to the Bone / Musculoskeletal Complications / Pain / Urinary Complications1
3Active Not RecruitingSupportive CareBone destruction / Prostate Cancer1
3Active Not RecruitingTreatmentCancer, Breast3
3Active Not RecruitingTreatmentComplete Traumatic Spinal Cord Injury / Spinal Cord Injuries (SCI)1
3Active Not RecruitingTreatmentComplex Regional Pain Syndrome (CRPS) / Complex Regional Pain Syndrome - Type 1 / Complex Regional Pain Syndrome Type I1
3Active Not RecruitingTreatmentTriple Negative Breast Cancer (TNBC)1
3CompletedPreventionCancer, Breast3
3CompletedPreventionLung Cancer Non-Small Cell Cancer (NSCLC)1
3CompletedPreventionBone destruction / Neoplasms, Breast1
3CompletedPreventionNon Small Cell Lung Carcinoma (NSCLC)1
3CompletedSupportive CareBone Metastases3
3CompletedSupportive CareCancer, Breast / Lung Cancers / Metastatic Cancers / Pain / Prostate Cancer1
3CompletedSupportive CareBone destruction / Cancer, Breast3
3CompletedSupportive CareHypercalcemia of Malignancy / Lung Cancers / Metastatic Cancers / Pain / Unspecified Adult Solid Tumor, Protocol Specific1
3CompletedSupportive CareOsteogenesis Imperfecta1
3CompletedTreatmentAvascular Necrosis of Femoral Head1
3CompletedTreatmentBone Loss / Cancer, Breast1
3CompletedTreatmentBone Marrow Oedema1
3CompletedTreatmentBreast Cancer With Bone Metastasis1
3CompletedTreatmentCancer Prostate1
3CompletedTreatmentCancer, Breast5
3CompletedTreatmentBone destruction / Crohn's Disease (CD) / Osteopenia1
3CompletedTreatmentFractures, Bone1
3CompletedTreatmentFunctional Outcomes / Prevention of BMD Loss After THR / Serum Markers of Bone Turnover1
3CompletedTreatmentBone destruction / Hip Fractures1
3CompletedTreatmentMale Osteoporosis1
3CompletedTreatmentMalignant Lymphomas / Non-Hodgkin's Lymphoma (NHL)1
3CompletedTreatmentMetastatic Cancers / Prostate Cancer2
3CompletedTreatmentMultiple Myeloma and Plasma Cell Neoplasm2
3CompletedTreatmentOsteopenia2
3CompletedTreatmentOsteoporosis, Post-Menopausal1
3CompletedTreatmentPaget's Disease of Bone2
3CompletedTreatmentPain1
3CompletedTreatmentPostmenopausal Osteoporosis (PMO)1
3CompletedTreatmentProstate Cancer3
3CompletedTreatmentTreatment of Bone Metastases1
3CompletedTreatmentBone destruction9
3CompletedTreatmentBone destruction / One to five years postmenopausal1
3Not Yet RecruitingTreatmentBone destruction / Thalassemia Majors (Beta-Thalassemia Major)1
3RecruitingPreventionLung Cancer Non-Small Cell Cancer (NSCLC) / Lung Cancers1
3RecruitingPreventionRheumatoid Arthritis1
3RecruitingSupportive CareMetastatic Renal Cell Carcinoma1
3RecruitingTreatmentEwing's Sarcoma (ES)1
3RecruitingTreatmentGiant Cell Tumors of Bone1
3RecruitingTreatmentSolitary Osseous Plasmacytoma1
3RecruitingTreatmentBone destruction1
3TerminatedTreatmentAIS Grade A to D / Being Diagnosed With a Spinal Cord Injury Less Than 12 Weeks of Etiology Stable / Bone Demineralization Lesions in the Injured Marrow / Female or Male Between 18 and 45 Years / Level of Injury C5 L2 / No Osteoporosis / No Pregnancy1
3TerminatedTreatmentBone Neoplasms / Neoplasms Metastasis / Pain2
3TerminatedTreatmentBreast Cancer With Bone Metastasis1
3TerminatedTreatmentCancer, Breast / Neoplasms Metastasis1
3TerminatedTreatmentBone destruction / Disseminated Sclerosis1
3TerminatedTreatmentMultiple Myeloma (MM)2
3TerminatedTreatmentMultiple Myeloma Stage I1
3TerminatedTreatmentProstate Cancer3
3TerminatedTreatmentSarcomas1
3Unknown StatusTreatmentCancer, Breast / Hypercalcemia of Malignancy / Metastatic Cancers1
3Unknown StatusTreatmentCancer, Breast / Metastatic Cancers1
3WithdrawnSupportive CareCancer, Breast / Hypercalcemia of Malignancy / Metastatic Cancers / Pain1
4Active Not RecruitingPreventionMultiple Myeloma (MM)1
4Active Not RecruitingPreventionBone destruction1
4Active Not RecruitingTreatmentPostmenopausal Osteoporosis (PMO)2
4CompletedPreventionBone Neoplasms1
4CompletedPreventionBone destruction / Fracture Bone / Transplantation, Liver1
4CompletedPreventionMultiple Myeloma (MM)1
4CompletedPreventionOsteoarthritis, Hip1
4CompletedPreventionProstate Cancer1
4CompletedPreventionThalassaemic disorders1
4CompletedTreatmentBone Metastases / High NTX Level / Lung Cancer Non-Small Cell Cancer (NSCLC)1
4CompletedTreatmentBone Metastasis / Cancer, Breast / Prostate Cancer1
4CompletedTreatmentBreast Cancer With Metastatic Bone Disease1
4CompletedTreatmentCancer, Breast1
4CompletedTreatmentCancer, Breast / Multiple Myeloma (MM) / Prostate Cancer1
4CompletedTreatmentCancers / Neoplasms Metastasis / Pain1
4CompletedTreatmentDisuse Osteoporosis1
4CompletedTreatmentFirst or Second Line HER2-negative Breast Cancer / Metastatic Disease Without Bone Metastasis1
4CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections1
4CompletedTreatmentHypocalcemia / Paget's Disease of the Bone1
4CompletedTreatmentLung Cancer Non-Small Cell Cancer (NSCLC) / Pleural Effusion, Malignant1
4CompletedTreatmentMultiple Myeloma (MM)1
4CompletedTreatmentNeoplasms Metastasis1
4CompletedTreatmentNeoplasms Metastasis / Renal Cell Adenocarcinoma1
4CompletedTreatmentOsteoporosis, Osteopenia1
4CompletedTreatmentOsteoporosis, Post-Menopausal1
4CompletedTreatmentPaget's Disease of Bone1
4CompletedTreatmentPaget's Disease of the Bone1
4CompletedTreatmentPost Menopausal Osteoporosis1
4CompletedTreatmentProstate Cancer6
4CompletedTreatmentProstate Cancer Patients With Bone Metastasis1
4CompletedTreatmentProstate Cancer With Bone Metastasis1
4CompletedTreatmentProstate Cancer With at Least One Bone Lesion in Patients Receiving Hormonal Therapy and Treatment With Bisphosphonates is Indicated1
4CompletedTreatmentRenal Osteodystrophy1
4CompletedTreatmentBone destruction3
4Not Yet RecruitingPreventionBariatric Surgery Candidate1
4Not Yet RecruitingTreatmentBone Metastasis / Lung Cancer Non-Small Cell Cancer (NSCLC)1
4Not Yet RecruitingTreatmentEarly-Stage Breast Cancer1
4Not Yet RecruitingTreatmentPostmenopausal Osteoporosis (PMO)1
4RecruitingTreatmentCancer, Breast / Metastasis / Prostate Cancer1
4RecruitingTreatmentMultiple Myeloma (MM)1
4RecruitingTreatmentOsteoporotic Fractures / Postmenopausal Osteoporosis (PMO)1
4RecruitingTreatmentProsthetic Fixation After Cementless Total Hip Arthroplasty1
4RecruitingTreatmentStress Fracture Ankle / Stress Fracture Foot1
4TerminatedTreatmentPrimary Hormone Receptor Negative Breast Cancer in Premenopausal Women1
4Unknown StatusDiagnosticMetastatic Breast Cancer (MBC)1
4Unknown StatusTreatmentBone Mineral Density / Bone Turnover Markers / Image Changes of Lumbar Fusion1
4Unknown StatusTreatmentMultiple Myeloma (MM)1
4WithdrawnTreatmentCystic Fibrosis (CF)1
4WithdrawnTreatmentMultiple Myeloma (MM)1
Not AvailableActive Not RecruitingSupportive CareBone destruction / Cancer, Breast1
Not AvailableActive Not RecruitingTreatmentEstrogen Receptor-Positive Breast Cancer / Invasive Ductal Breast Carcinoma / Progesterone Receptor-positive Breast Cancer / Stage IA Breast Cancer / Stage IB Breast Cancer / Stage IIA Breast Cancer / Stage IIB Breast Cancer1
Not AvailableActive Not RecruitingTreatmentOsteonecrosis1
Not AvailableCompletedNot AvailableBone Metastasis / Metastatic Hormone Refractory Prostate Cancer1
Not AvailableCompletedNot AvailableCancer, Breast1
Not AvailableCompletedNot AvailableBone destruction / Multiple Disabilities1
Not AvailableCompletedNot AvailableMultiple Myeloma (MM)1
Not AvailableCompletedNot AvailableOsteoporosis, Post-Menopausal1
Not AvailableCompletedPreventionBone destruction / Cancer, Breast1
Not AvailableCompletedScreeningProstate Cancer1
Not AvailableCompletedTreatmentBone Density / Prostatic Neoplasms1
Not AvailableCompletedTreatmentBone destruction / Bone Loss / Fragility Fractures1
Not AvailableCompletedTreatmentCancers / Hypercalcemia / Pain1
Not AvailableCompletedTreatmentImpaired Renal Function1
Not AvailableCompletedTreatmentPostmenopausal Osteoporosis (PMO)1
Not AvailableCompletedTreatmentProstate Cancer1
Not AvailableCompletedTreatmentBone destruction2
Not AvailableEnrolling by InvitationNot AvailableAtypical Femoral Fractures / Bisphosphonate Therapy / Bone destruction1
Not AvailableRecruitingTreatmentBone Loss / Neoplasms, Breast1
Not AvailableTerminatedTreatmentMultiple Myeloma (MM)1
Not AvailableUnknown StatusNot AvailableCancer, Breast1
Not AvailableUnknown StatusPreventionBone destruction / Transplantation, Liver1
Not AvailableUnknown StatusSupportive CareCancer, Breast / Hypercalcemia of Malignancy / Metastatic Cancers / Musculoskeletal Complications / Pain1
Not AvailableWithdrawnNot AvailableCancer, Breast1
Not AvailableWithdrawnDiagnosticMusculoskeletal Complications / Neoplasms, Malignant1
Not AvailableWithdrawnSupportive CareBone Marrow Transplant (BMT) / Hematopoietic Stem Cell Transplant (HSCT)1

Pharmacoeconomics

Manufacturers
  • Novartis pharmaceuticals corp
Packagers
  • Novartis AG
Dosage forms
FormRouteStrength
Injection, solutionIntravenous5 mg/100ml
SolutionIntravenous5 mg
InjectionIntravenous4 mg/100mL
InjectionIntravenous4 mg/5mL
InjectionIntravenous5 mg/100mL
Injection, solutionIntravenous0.04 mg/1mL
Injection, solutionIntravenous0.05 mg/1mL
Injection, solution, concentrateIntravenous0.8 mg/1mL
Kit4 mg/5mL
SolutionIntravenous5 mg/100mL
Injection, solutionIntravenous4 mg/100ml
Injection, solution, concentrateIntravenous4 mg/5ml
Injection, solutionIntravenous5 mg
Injection, solution, concentrateIntravenous4 mg/100mL
SolutionIntravenous4 mg
Powder, for solutionIntravenous4 mg
Prices
Unit descriptionCostUnit
Zometa 4 mg/5ml Concentrate 5ml Vial1095.69USD vial
Reclast 5 mg/100ml Solution13.39USD ml
Reclast 5 mg/100 ml solution12.88USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US4939130No1993-03-022013-03-02Us
CA1338937No1997-02-252014-02-25Canada
CA1338895No1997-02-042014-02-04Canada
US8324189Yes2005-11-292025-11-29Us
US7932241Yes2008-08-052028-08-05Us
US8052987No2003-10-272023-10-27Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySparingly solubleNot Available
logP-4.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility3.27 mg/mLALOGPS
logP-0.93ALOGPS
logP-3.9ChemAxon
logS-1.9ALOGPS
pKa (Strongest Acidic)0.66ChemAxon
pKa (Strongest Basic)6.67ChemAxon
Physiological Charge-2ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count5ChemAxon
Polar Surface Area153.11 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity52.16 m3·mol-1ChemAxon
Polarizability20.1 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.9723
Blood Brain Barrier+0.825
Caco-2 permeable-0.6418
P-glycoprotein substrateNon-substrate0.5602
P-glycoprotein inhibitor INon-inhibitor0.943
P-glycoprotein inhibitor IINon-inhibitor0.9961
Renal organic cation transporterNon-inhibitor0.9366
CYP450 2C9 substrateNon-substrate0.8319
CYP450 2D6 substrateNon-substrate0.8201
CYP450 3A4 substrateNon-substrate0.7551
CYP450 1A2 substrateNon-inhibitor0.8531
CYP450 2C9 inhibitorNon-inhibitor0.8576
CYP450 2D6 inhibitorNon-inhibitor0.8935
CYP450 2C19 inhibitorNon-inhibitor0.8319
CYP450 3A4 inhibitorNon-inhibitor0.9334
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9904
Ames testNon AMES toxic0.5596
CarcinogenicityNon-carcinogens0.8194
BiodegradationNot ready biodegradable0.5431
Rat acute toxicity2.3342 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8515
hERG inhibition (predictor II)Non-inhibitor0.8616
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - DI-ESI-qTof , NegativeLC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as bisphosphonates. These are organic compounds containing two phosphonate groups linked together through a carbon atoms.
Kingdom
Organic compounds
Super Class
Organic acids and derivatives
Class
Organic phosphonic acids and derivatives
Sub Class
Bisphosphonates
Direct Parent
Bisphosphonates
Alternative Parents
N-substituted imidazoles / Organic phosphonic acids / Heteroaromatic compounds / Azacyclic compounds / Organopnictogen compounds / Organophosphorus compounds / Organooxygen compounds / Organonitrogen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
Bisphosphonate / N-substituted imidazole / Azole / Imidazole / Organophosphonic acid / Heteroaromatic compound / Azacycle / Organoheterocyclic compound / Organic nitrogen compound / Organophosphorus compound
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
imidazoles, 1,1-bis(phosphonic acid) (CHEBI:46557)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Poly(a) rna binding
Specific Function
Key enzyme in isoprenoid biosynthesis which catalyzes the formation of farnesyl diphosphate (FPP), a precursor for several classes of essential metabolites including sterols, dolichols, carotenoids...
Gene Name
FDPS
Uniprot ID
P14324
Uniprot Name
Farnesyl pyrophosphate synthase
Molecular Weight
48275.03 Da
References
  1. 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:11160603]
  2. Glickman JF, Schmid A: Farnesyl pyrophosphate synthase: real-time kinetics and inhibition by nitrogen-containing bisphosphonates in a scintillation assay. Assay Drug Dev Technol. 2007 Apr;5(2):205-14. [PubMed:17477829]
  3. Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AH: Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7. Epub 2007 May 29. [PubMed:17535895]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Metal ion binding
Specific Function
Catalyzes the trans-addition of the three molecules of IPP onto DMAPP to form geranylgeranyl pyrophosphate, an important precursor of carotenoids and geranylated proteins.
Gene Name
GGPS1
Uniprot ID
O95749
Uniprot Name
Geranylgeranyl pyrophosphate synthase
Molecular Weight
34870.625 Da
References
  1. Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, Kuo CJ, Yin F, Oldfield E, Wang AH: Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10022-7. Epub 2007 May 29. [PubMed:17535895]
Kind
Small molecule
Organism
Human
Pharmacological action
Yes
Actions
Antagonist
References
  1. Jahnke W, Henry C: An in vitro assay to measure targeted drug delivery to bone mineral. ChemMedChem. 2010 May 3;5(5):770-6. doi: 10.1002/cmdc.201000016. [PubMed:20209564]
  2. Nancollas GH, Tang R, Phipps RJ, Henneman Z, Gulde S, Wu W, Mangood A, Russell RG, Ebetino FH: Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone. 2006 May;38(5):617-27. Epub 2005 Jul 20. [PubMed:16046206]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Transporter activity
Specific Function
Mediates export of organic anions and drugs from the cytoplasm. Mediates ATP-dependent transport of glutathione and glutathione conjugates, leukotriene C4, estradiol-17-beta-o-glucuronide, methotre...
Gene Name
ABCC1
Uniprot ID
P33527
Uniprot Name
Multidrug resistance-associated protein 1
Molecular Weight
171589.5 Da
References
  1. Yildiz M, Celik-Ozenci C, Akan S, Akan I, Sati L, Demir R, Savas B, Ozben T, Samur M, Ozdogan M, Artac M, Bozcuk H: Zoledronic acid is synergic with vinblastine to induce apoptosis in a multidrug resistance protein-1 dependent way: an in vitro study. Cell Biol Int. 2006 Mar;30(3):278-82. Epub 2006 Feb 2. [PubMed:16458542]

Drug created on June 13, 2005 07:24 / Updated on September 25, 2018 17:45