Details
| Stereochemistry | ABSOLUTE |
| Molecular Formula | C24H29N5O3 |
| Molecular Weight | 435.5188 |
| Optical Activity | UNSPECIFIED |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 0 |
| Charge | 0 |
SHOW SMILES / InChI
SMILES
CCCCC(=O)N(CC1=CC=C(C=C1)C2=CC=CC=C2C3=NN=NN3)[C@@H](C(C)C)C(O)=O
InChI
InChIKey=ACWBQPMHZXGDFX-QFIPXVFZSA-N
InChI=1S/C24H29N5O3/c1-4-5-10-21(30)29(22(16(2)3)24(31)32)15-17-11-13-18(14-12-17)19-8-6-7-9-20(19)23-25-27-28-26-23/h6-9,11-14,16,22H,4-5,10,15H2,1-3H3,(H,31,32)(H,25,26,27,28)/t22-/m0/s1
| Molecular Formula | C24H29N5O3 |
| Molecular Weight | 435.5188 |
| Charge | 0 |
| Count |
|
| Stereochemistry | ABSOLUTE |
| Additional Stereochemistry | No |
| Defined Stereocenters | 1 / 1 |
| E/Z Centers | 0 |
| Optical Activity | UNSPECIFIED |
DescriptionSources: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/entresto.pdfhttp://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021283s50lbl.pdfhttps://www.ncbi.nlm.nih.gov/pubmed/25052956Curator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/mesh/2009869
Sources: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/entresto.pdfhttp://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021283s50lbl.pdfhttps://www.ncbi.nlm.nih.gov/pubmed/25052956
Curator's Comment: description was created based on several sources, including
https://www.ncbi.nlm.nih.gov/mesh/2009869
There is no information in the literature about pharmacological and biological application of definite isomer of valsatran, R – form (also known as VALSARTAN, D- or CGP-49309). However there were found, that in the tablets of valsartan, which are used to treat high blood pressure and to heart failure, the R-enantiomer was an impurity.
CNS Activity
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26663387https://www.ncbi.nlm.nih.gov/pubmed/23227311
Curator's Comment: LBQ657 (an LCZ696 metabolite) achieves CSF concentrations sufficient to inhibit neprilysin, but LCZ696 did not cause changes in CSF levels of aggregable Abeta isoforms (1-42 and 1-40) compared with placebo
Originator
Sources: https://www.novartis.com/news/media-releases/novartis-new-heart-failure-medicine-lcz696-now-called-entrestotm-approved-fdahttps://www.ncbi.nlm.nih.gov/pubmed/8505092
Curator's Comment: # Novartis
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
Target ID: CHEMBL227 |
2.38 nM [Ki] | ||
Target ID: CHEMBL1944 |
2.3 nM [IC50] | ||
Target ID: CHEMBL227 |
2.43 nM [IC50] |
Conditions
| Condition | Modality | Targets | Highest Phase | Product |
|---|---|---|---|---|
| Primary | ENTRESTO Approved UseENTRESTO is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker, indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. ENTRESTO is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB. Launch Date2015 |
|||
| Primary | DIOVAN Approved UseDiovan is an angiotensin II receptor blocker (ARB) indicated for:
Treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (1.1)
Treatment of heart failure (NYHA class II-IV); Diovan significantly reduced hospitalization for heart failure (1.2)
Reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction (1.3) Launch Date2011 |
|||
| Primary | DIOVAN Approved UseDiovan is an angiotensin II receptor blocker (ARB) indicated for:
Treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (1.1)
Treatment of heart failure (NYHA class II-IV); Diovan significantly reduced hospitalization for heart failure (1.2)
Reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction (1.3) Launch Date2011 |
|||
| Palliative | DIOVAN Approved UseDiovan is an angiotensin II receptor blocker (ARB) indicated for:
Treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions (1.1)
Treatment of heart failure (NYHA class II-IV); Diovan significantly reduced hospitalization for heart failure (1.2)
Reduction of cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction (1.3) Launch Date2011 |
Cmax
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
2.141 μg/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21617777 |
160 mg single, oral dose: 160 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
2808 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27128457 |
80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
5756 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27128457 |
80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
AUC
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
22.56 μg × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21617777 |
160 mg single, oral dose: 160 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
20650 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27128457 |
80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
34310 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27128457 |
80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
T1/2
| Value | Dose | Co-administered | Analyte | Population |
|---|---|---|---|---|
9.55 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/21617777 |
160 mg single, oral dose: 160 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN |
|
8.45 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27128457 |
80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
|
8 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/27128457 |
80 mg single, oral dose: 80 mg route of administration: Oral experiment type: SINGLE co-administered: |
VALSARTAN plasma | Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED |
PubMed
| Title | Date | PubMed |
|---|---|---|
| Pharmacodynamic and Pharmacokinetic Profiles of Sacubitril/Valsartan (LCZ696) in Patients with Heart Failure and Reduced Ejection Fraction. | 2016-08 |
|
| LCZ696, an angiotensin receptor-neprilysin inhibitor, improves cardiac function with the attenuation of fibrosis in heart failure with reduced ejection fraction in streptozotocin-induced diabetic mice. | 2016-04 |
|
| Influence of Ejection Fraction on Outcomes and Efficacy of Sacubitril/Valsartan (LCZ696) in Heart Failure with Reduced Ejection Fraction: The Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Trial. | 2016-03 |
|
| LCZ696 (Valsartan/Sacubitril)--A Possible New Treatment for Hypertension and Heart Failure. | 2016-01 |
|
| Sacubitril/valsartan (LCZ696) for the treatment of heart failure. | 2016 |
|
| LCZ696 : a new paradigm for the treatment of heart failure? | 2015-02 |
|
| Determination of the R-enantiomer of valsartan in pharmaceutical formulation by capillary electrophoresis. | 2015 |
|
| Efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Asian patients with hypertension: a randomized, double-blind, placebo-controlled study. | 2014-04 |
|
| Enantiomeric LC separation of valsartan on amylose based stationary phase. | 2009-08 |
|
| Development and validation of chiral high-performance liquid chromatographic methods for the quantitation of valsartan and of the tosylate of valinebenzyl ester. | 1996-11-08 |
|
| Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: a comparative study of the efficacy and safety against amlodipine. | 1996-09 |
|
| Remodelling of resistance arteries in genetically hypertensive rats by treatment with valsartan, an angiotensin II receptor antagonist. | 1996-06-01 |
|
| Binding of valsartan to mammalian angiotensin AT1 receptors. | 1995-11-10 |
|
| Angiotensin II receptor blockade with single doses of valsartan in healthy, normotensive subjects. | 1994 |
|
| Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT1-receptor subtype. | 1993-10 |
Sample Use Guides
The recommended starting dose of ENTRESTO, previously known as LCZ696, is 49/51 mg (sacubitril/valsartan) twice-daily. Double the dose of ENTRESTO after 2 to 4 weeks to the target maintenance dose of 97/103 mg (sacubitril/valsartan) twice-daily, as tolerated by the patient.
Route of Administration:
Oral
In Vitro Use Guide
Sources: Von Lueder TG, Wang B, Kompa A, Huang L, Webb R, Jordan P, Krum H. ARNi, combined neprilysin and angiotensin receptor inhibition augments anti-fibrotic and anti-hypertrophic effects in vitro. Eur.Heart J. 2012;33:P5834.
Curator's Comment: ...
30 nM to 1 uM valsartan (LCZ696 component) in the presence of 10 uM LBQ657 (Sacubitril (LCZ696 component) metabolite) demonstrate anti-fibrotic and anti-hypertrophic effects on rat cardiac fibroblasts and cardiomyocytes, respectively, cultured with 100 nM angiotensin II
| Substance Class |
Chemical
Created
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| Record UNII |
80M03YXJ7I
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Validated (UNII)
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WHO-ATC |
C09CA03
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EMA ASSESSMENT REPORTS |
IMPRADA-HCT (WITHDRAWN: HYPERTENSION)
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WHO-ATC |
C10BX10
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EMA ASSESSMENT REPORTS |
EXFORGE (AUTHORIZED: HYPERTENSION)
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FDA ORPHAN DRUG |
494115
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WHO-VATC |
QC09CA03
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NDF-RT |
N0000175561
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WHO-ATC |
C09DX02
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EMA ASSESSMENT REPORTS |
COPALIA (AUTHORIZED: HYPERTENSION)
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WHO-ATC |
C09DX01
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WHO-VATC |
QC09DA03
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EMA ASSESSMENT REPORTS |
EXFORGE-HCT (AUTHORIZED: HYPERTENSION)
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NCI_THESAURUS |
C66930
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WHO-ATC |
C09DB08
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EMA ASSESSMENT REPORTS |
DARFIRO-HCT (AUTHORIZED: HYPERTENSION)
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LIVERTOX |
NBK547944
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EMA ASSESSMENT REPORTS |
COPALIA-HCT (AUTHORIZED: HYPERTENSION)
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WHO-ATC |
C09DA03
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NDF-RT |
N0000000070
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DAFIRO (AUTHORIZED: HYPERTENSION)
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WHO-VATC |
QC09DX01
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IMPRIDA (AUTHORIZED: HYPERTENSION)
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WHO-ATC |
C09DX05
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WHO-ATC |
C09DX04
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WHO-VATC |
QC09DX02
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WHO-ATC |
C09DB01
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WHO-VATC |
QC09DB01
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758927
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80M03YXJ7I
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137862-53-4
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3937
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CHEMBL1069
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80M03YXJ7I
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C081489
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VALSARTAN
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100000088000
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1708762
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DB00177
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C47781
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Valsartan
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m11372
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60846
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SUB00017MIG
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| Related Record | Type | Details | ||
|---|---|---|---|---|
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TRANSPORTER -> INHIBITOR | |||
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TRANSPORTER -> INHIBITOR | |||
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TRANSPORTER -> INHIBITOR | |||
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TARGET -> INHIBITOR | |||
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SALT/SOLVATE -> PARENT | |||
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BINDER->LIGAND |
BINDING
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BASIS OF STRENGTH->SUBSTANCE |
ASSAY (HPLC)
USP
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BASIS OF STRENGTH->SUBSTANCE |
ASSAY (TITRATION)
EP
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TRANSPORTER -> INHIBITOR | |||
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SALT/SOLVATE -> PARENT |
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TRANSPORTER -> INHIBITOR | |||
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TRANSPORTER -> INHIBITOR | |||
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SALT/SOLVATE -> PARENT |
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| Related Record | Type | Details | ||
|---|---|---|---|---|
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METABOLITE INACTIVE -> PARENT | |||
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METABOLITE INACTIVE -> PARENT |
Valsartan was metabolized to a small extent only. The only notable metabolite in plasma, urine and faecs
MAJOR
FECAL; PLASMA; URINE
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| Related Record | Type | Details | ||
|---|---|---|---|---|
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IMPURITY -> PARENT |
CHROMATOGRAPHIC PURITY (HPLC/UV)
USP
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IMPURITY -> PARENT | |||
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IMPURITY -> PARENT |
Probable human carcinogen.
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IMPURITY -> PARENT | |||
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IMPURITY -> PARENT |
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IMPURITY -> PARENT |
UNSPECIFIED
EP
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IMPURITY -> PARENT | |||
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IMPURITY -> PARENT |
CHROMATOGRAPHIC PURITY (HPLC/UV)
EP
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IMPURITY -> PARENT |
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IMPURITY -> PARENT |
Priority toxic pollutant.
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IMPURITY -> PARENT |
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IMPURITY -> PARENT |
CHROMATOGRAPHIC PURITY (HPLC/UV)
USP
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IMPURITY -> PARENT |
CHROMATOGRAPHIC PURITY (HPLC/UV)
EP
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IMPURITY -> PARENT |
CHROMATOGRAPHIC PURITY (HPLC/UV)
USP
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IMPURITY -> PARENT |
NDMA is an organic chemical that is in a family of potent carcinogens.
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| Related Record | Type | Details | ||
|---|---|---|---|---|
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ACTIVE MOIETY |
| Name | Property Type | Amount | Referenced Substance | Defining | Parameters | References |
|---|---|---|---|---|---|---|
| Volume of Distribution | PHARMACOKINETIC |
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| Route of Elimination | PHARMACOKINETIC |
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ROUTE OF ADMINISTRATION: ORAL |
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| MAXIMUM TOLERATED DOSE | TOXICITY |
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| PROTEIN BINDING | PHARMACOKINETIC |
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| Route of Elimination | PHARMACOKINETIC |
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ROUTE OF ADMINISTRATION: ORAL |
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| RENAL CLEARANCE | PHARMACOKINETIC |
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| Biological Half-life | PHARMACOKINETIC |
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