Details
Stereochemistry | ACHIRAL |
Molecular Formula | C29H27F3N6O |
Molecular Weight | 532.5595 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 0 |
Charge | 0 |
SHOW SMILES / InChI
SMILES
CN1CCN(CC2=CC=C(NC(=O)C3=CC=C(C)C(=C3)C#CC4=CN=C5C=CC=NN45)C=C2C(F)(F)F)CC1
InChI
InChIKey=PHXJVRSECIGDHY-UHFFFAOYSA-N
InChI=1S/C29H27F3N6O/c1-20-5-6-22(16-21(20)8-10-25-18-33-27-4-3-11-34-38(25)27)28(39)35-24-9-7-23(26(17-24)29(30,31)32)19-37-14-12-36(2)13-15-37/h3-7,9,11,16-18H,12-15,19H2,1-2H3,(H,35,39)
Ponatinib (trade name Iclusig, previously AP24534) is developed by ARIAD Pharmaceuticals for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome–positive (Ph ) acute lymphoblastic leukemia (ALL). Ponatinib has been designed to be effective against these types of tumors. The United States Food and Drug Administration approved the drug as a candidate in 2012, but temporarily suspended sales on 31 October 2013 because of "the risk of life-threatening blood clots and severe narrowing of blood vessels". This suspension was partially lifted on Dec. 20, 2013 with ponatinib being issued revised prescribing information, a new "Black Box Warning" and a "Risk Evaluation and Mitigation Strategy" in place to better evaluate the risks and benefits of using the drug. Ponatinib is an orally bioavailable multitargeted receptor tyrosine kinase (RTK) inhibitor with potential antiangiogenic and antineoplastic activities. Ponatinib inhibits unmutated and all mutated forms of Bcr-Abl, including T315I, the highly drug therapy-resistant missense mutation of Bcr-Abl. This agent also inhibits other tyrosine kinases including those associated with vascular endothelial growth factor receptors (VEGFRs) and fibroblast growth factor receptors (FGFRs); in addition, it inhibits the tyrosine kinase receptor TIE2 and FMS-related tyrosine kinase receptor-3 (Flt3). RTK inhibition by ponatinib may result in the inhibition of cellular proliferation and angiogenesis and may induce cell death. Bcr-Abl is a fusion tyrosine kinase encoded by the Philadelphia chromosome.
CNS Activity
Originator
Approval Year
Targets
Primary Target | Pharmacology | Condition | Potency |
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Target ID: 12345.0 Gene ID: 25400.0 Gene Symbol: Camk2a Target Organism: Rattus norvegicus (Rat) |
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Target ID: P00594 Gene ID: NA Gene Symbol: PLA2G1B |
0.4 nM [IC50] | ||
Target ID: GO:0000001 Target Organism: Homo sapiens (Human) Sources: http://helloworld.com |
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Target ID: 123.0 Sources: https://pubmed.ncbi.nlm.nih.gov/32915792/ |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
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Primary | Iclusig Approved UseTo treat adults with chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), two rare blood and bone marrow diseases. Launch Date2020 |
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Sources: https://pubmed.ncbi.nlm.nih.gov/1373760 |
Palliative | Launch Date1970 |
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Inactive Ingredient | Approved UseTo treat adults with chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph ALL), two rare blood and bone marrow diseases. Launch Date2013 |
Cmax
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
73 ng/mL |
45 mg 1 times / day steady-state, oral dose: 45 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
PONATINIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
183.1 nM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23190221 |
60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
PONATINIB blood | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
73 ng/mL |
45 mg 1 times / day steady-state, oral dose: 45 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
PONATINIB unknown | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
AUC
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1253 ng × h/mL |
45 mg 1 times / day steady-state, oral dose: 45 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
PONATINIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
2856 nM × h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23190221 |
60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
PONATINIB blood | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
1253 ng × h/mL |
45 mg 1 times / day steady-state, oral dose: 45 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
PONATINIB unknown | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
T1/2
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
24 h |
45 mg 1 times / day steady-state, oral dose: 45 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
PONATINIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
19.7 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/23190221 |
60 mg 1 times / day steady-state, oral dose: 60 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
PONATINIB blood | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
Funbound
Value | Dose | Co-administered | Analyte | Population |
---|---|---|---|---|
1% |
45 mg 1 times / day steady-state, oral dose: 45 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
PONATINIB plasma | Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN |
|
1% |
45 mg 1 times / day steady-state, oral dose: 45 mg route of administration: Oral experiment type: STEADY-STATE co-administered: |
PONATINIB unknown | Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN |
Doses
Dose | Population | Adverse events |
---|---|---|
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
Disc. AE: Infection, Thrombocytopenia... AEs leading to discontinuation/dose reduction: Infection (1%) Sources: Thrombocytopenia (30%) Neutropenia (13%) Lipase increased (12%) Rash (11%) Abdominal pain (11%) Pancreatitis (6%) ALT increased (6%) AST increased (6%) GGT increased (6%) Myocardial ischemia (serious, 5%) Arterial thrombosis (serious, 34 patients) Ischemia cerebral (serious, 8 patients) Peripheral arterial ischemia (serious, 7 patients) Arterial stenosis (serious, 5%) Myocardial infarction (serious, 14 patients) Cerebrovascular event (serious, 2%) Extremity necrosis (serious, 3 patients) Thrombocytopenia (4%) |
60 mg 1 times / day multiple, oral Recommended,MTD,Overdose Dose: 60 mg, 1 times / day Route: oral Route: multiple Dose: 60 mg, 1 times / day Sources: |
unhealthy n = 19 Health Status: unhealthy Population Size: 19 Sources: |
Disc. AE: Ischemia... AEs leading to discontinuation/dose reduction: Ischemia (serious, 4 patients) Sources: |
60 mg 1 times / day multiple, oral Dose: 60 mg, 1 times / day Route: oral Route: multiple Dose: 60 mg, 1 times / day Sources: |
unhealthy n = 19 Health Status: unhealthy Population Size: 19 Sources: |
DLT: Blood amylase increased, Fatigue... Dose limiting toxicities: Blood amylase increased (grade 3-4, 4 patients) Sources: Fatigue (grade 3, 1 patient) Alanine aminotransferase increased (grade 3, 1 patient) Aspartate aminotransferase increased (grade 3, 1 patient) Lipase increased (grade 3-4, 4 patients) |
AEs
AE | Significance | Dose | Population |
---|---|---|---|
Infection | 1% Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
Abdominal pain | 11% Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
Rash | 11% Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
Lipase increased | 12% Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
Neutropenia | 13% Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
Thrombocytopenia | 30% Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
Thrombocytopenia | 4% Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
ALT increased | 6% Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
AST increased | 6% Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
GGT increased | 6% Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
Pancreatitis | 6% Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
Myocardial infarction | serious, 14 patients Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
Cerebrovascular event | serious, 2% Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
Extremity necrosis | serious, 3 patients Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
Arterial thrombosis | serious, 34 patients Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
Arterial stenosis | serious, 5% Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
Myocardial ischemia | serious, 5% Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
Peripheral arterial ischemia | serious, 7 patients Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
Ischemia cerebral | serious, 8 patients Disc. AE |
45 mg 1 times / day steady, oral Recommended Dose: 45 mg, 1 times / day Route: oral Route: steady Dose: 45 mg, 1 times / day Sources: |
unhealthy n = 449 Health Status: unhealthy Population Size: 449 Sources: |
Ischemia | serious, 4 patients Disc. AE |
60 mg 1 times / day multiple, oral Recommended,MTD,Overdose Dose: 60 mg, 1 times / day Route: oral Route: multiple Dose: 60 mg, 1 times / day Sources: |
unhealthy n = 19 Health Status: unhealthy Population Size: 19 Sources: |
Alanine aminotransferase increased | grade 3, 1 patient DLT |
60 mg 1 times / day multiple, oral Dose: 60 mg, 1 times / day Route: oral Route: multiple Dose: 60 mg, 1 times / day Sources: |
unhealthy n = 19 Health Status: unhealthy Population Size: 19 Sources: |
Aspartate aminotransferase increased | grade 3, 1 patient DLT |
60 mg 1 times / day multiple, oral Dose: 60 mg, 1 times / day Route: oral Route: multiple Dose: 60 mg, 1 times / day Sources: |
unhealthy n = 19 Health Status: unhealthy Population Size: 19 Sources: |
Fatigue | grade 3, 1 patient DLT |
60 mg 1 times / day multiple, oral Dose: 60 mg, 1 times / day Route: oral Route: multiple Dose: 60 mg, 1 times / day Sources: |
unhealthy n = 19 Health Status: unhealthy Population Size: 19 Sources: |
Blood amylase increased | grade 3-4, 4 patients DLT |
60 mg 1 times / day multiple, oral Dose: 60 mg, 1 times / day Route: oral Route: multiple Dose: 60 mg, 1 times / day Sources: |
unhealthy n = 19 Health Status: unhealthy Population Size: 19 Sources: |
Lipase increased | grade 3-4, 4 patients DLT |
60 mg 1 times / day multiple, oral Dose: 60 mg, 1 times / day Route: oral Route: multiple Dose: 60 mg, 1 times / day Sources: |
unhealthy n = 19 Health Status: unhealthy Population Size: 19 Sources: |
Overview
CYP3A4 | CYP2C9 | CYP2D6 | hERG |
---|---|---|---|
OverviewOther
Drug as perpetrator
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
little [IC50 10.8 uM] | ||||
little [IC50 11.6 uM] | ||||
little [IC50 13.3 uM] | ||||
little [IC50 5.2 uM] | ||||
little [IC50 5.6 uM] | ||||
little [IC50 6.1 uM] | ||||
little [IC50 8.3 uM] | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
no | ||||
yes [Activation 0.6 uM] | ||||
yes [IC50 0.013 uM] | ||||
yes [IC50 0.49 uM] | ||||
yes [IC50 32 uM] |
Drug as victim
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
major | yes (co-administration study) Comment: ketoconazole increased cmax of ponatinib by 47%, auc by 78% |
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minor | ||||
minor | ||||
minor | ||||
no | ||||
no | ||||
no | ||||
weak | ||||
weak |
Tox targets
Target | Modality | Activity | Metabolite | Clinical evidence |
---|---|---|---|---|
PubMed
Title | Date | PubMed |
---|---|---|
Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. | 2012 Mar |
|
Ponatinib may overcome resistance of FLT3-ITD harbouring additional point mutations, notably the previously refractory F691I mutation. | 2012 May |
|
Ponatinib as targeted therapy for FGFR1 fusions associated with the 8p11 myeloproliferative syndrome. | 2013 Jan |
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Ponatinib as targeted therapy for FGFR1 fusions associated with the 8p11 myeloproliferative syndrome. | 2013 Jan |
|
A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. | 2015 Dec |
Sample Use Guides
45 mg taken orally once daily with or without food
Route of Administration:
Oral
Ponatinib inhibited the in vitro tyrosine kinase activity of ABL and T315I mutant ABL with IC50 concentrations of 0.4 and 2.0 nM, respectively. Ponatinib inhibited the in vitro activity of additional kinases with IC50 concentrations between 0.1 and 20 nM, including members of the VEGFR, PDGFR, FGFR, EPH receptors and SRC families of kinases, and KIT, RET, TIE2, and FLT3. Ponatinib inhibited the in vitro viability of cells expressing native or mutant BCR-ABL, including T315I.
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Classification Tree | Code System | Code | ||
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FDA ORPHAN DRUG |
466714
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NCI_THESAURUS |
C155700
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LIVERTOX |
NBK548131
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FDA ORPHAN DRUG |
294809
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FDA ORPHAN DRUG |
294709
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NCI_THESAURUS |
C1742
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WHO-ATC |
L01XE24
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NDF-RT |
N0000175605
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WHO-VATC |
QL01XE24
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EMA ASSESSMENT REPORTS |
ICLUSING (AUTHORIZED: LEUKEMIA, MYELOID)
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PONATINIB
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24826799
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78543
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C95777
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5890
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4340891KFS
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C545373
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Ponatinib
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DTXSID50241426
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XX-34
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CHEMBL1171837
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m11700
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SUB91901
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DB08901
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4340891KFS
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1364347
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4716
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ACTIVE MOIETY
METABOLITE (PARENT)
METABOLITE ACTIVE (PARENT)
METABOLITE INACTIVE (PARENT)
SALT/SOLVATE (PARENT)