Welcome to DrugBank 4.0! If you prefer, you can still go back to version 3.0.
Identification
NameAdefovir Dipivoxil
Accession NumberDB00718  (APRD00781)
Typesmall molecule
Groupsapproved, investigational
Description

Adefovir dipivoxil, previously called bis-POM PMEA, with trade names Preveon and Hepsera, is an orally-administered acyclic nucleotide analog reverse transcriptase inhibitor (ntRTI) used for treatment of hepatitis B. It is ineffective against HIV-1. [Wikipedia] Adefovir dipivoxil is the diester prodrug of adefovir.

Structure
Thumb
Synonyms
SynonymLanguageCode
AdéfovirFrenchINN
AdefovirGerman/SpanishINN
Adefovir PivoxilNot AvailableJAN
AdefovirumLatinINN
SaltsNot Available
Brand names
NameCompany
A Di XianThe United Laboratories Ltd
A Gan DingFujian Guangsheng Tang
AdeseraCipla
AdfovirSun Pharmaceutical Industries Ltd.
AiluweiChangzheng-Xinkai
AntivaSquare
BiovirIvax
Dai DingTianjin Institute of Pharmaceutical Research
DingheLukang
HepseraGilead Sciences, Inc.
InfovirIncepta
JiuleFovir Pharm
LifuzhiJiangsu TianShiLi BeiTe Pharmaceutical Co., Ltd.
Ming ZhengChia Tai Tianqing
NafaseraVidipha
PreveonGilead Sciences, Inc.
PymefovirPMP
XinfunuoSL Pharm
YilaifenQilu
Brand mixturesNot Available
Categories
CAS number142340-99-6
WeightAverage: 501.4705
Monoisotopic: 501.198849537
Chemical FormulaC20H32N5O8P
InChI KeyInChIKey=WOZSCQDILHKSGG-UHFFFAOYSA-N
InChI
InChI=1S/C20H32N5O8P/c1-19(2,3)17(26)30-11-32-34(28,33-12-31-18(27)20(4,5)6)13-29-8-7-25-10-24-14-15(21)22-9-23-16(14)25/h9-10H,7-8,11-13H2,1-6H3,(H2,21,22,23)
IUPAC Name
[({[2-(6-amino-9H-purin-9-yl)ethoxy]methyl}({[(2,2-dimethylpropanoyl)oxy]methoxy})phosphoryl)oxy]methyl 2,2-dimethylpropanoate
SMILES
CC(C)(C)C(=O)OCOP(=O)(COCCN1C=NC2=C(N)N=CN=C12)OCOC(=O)C(C)(C)C
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassImidazopyrimidines
SubclassPurines and Purine Derivatives
Direct parentPurines and Purine Derivatives
Alternative parentsAminopyrimidines and Derivatives; Primary Aromatic Amines; Phosphonic Acid Esters; Dicarboxylic Acids and Derivatives; N-substituted Imidazoles; Carboxylic Acid Esters; Enolates; Polyamines; Ethers
Substituentsaminopyrimidine; primary aromatic amine; phosphonic acid ester; dicarboxylic acid derivative; pyrimidine; n-substituted imidazole; imidazole; azole; phosphonic acid derivative; carboxylic acid ester; polyamine; carboxylic acid derivative; ether; enolate; primary amine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the purines and purine derivatives. These are aromatic heterocyclic compounds containing a purine moiety, which is formed a pyrimidine-ring ring fused to an imidazole ring.
Pharmacology
IndicationFor the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
PharmacodynamicsAdefovir dipivoxil a diester prodrug of adefovir. Adefovir is an acyclic nucleotide analog with activity against human hepatitis B virus (HBV). The concentration of adefovir that inhibited 50% of viral DNA synthesis (IC50) in vitro ranged from 0.2 to 2.5 μM in HBV transfected human hepatoma cell lines. The combination of adefovir with lamivudine showed additive anti-HBV activity.
Mechanism of actionAdefovir dipivoxil is a prodrug of adefovir. Adefovir is an acyclic nucleotide analog of adenosine monophosphate which is phosphorylated to the active metabolite adefovir diphosphate by cellular kinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. The inhibition constant (Ki) for adefovir diphosphate for HBV DNA polymerase was 0.1 μM. Adefovir diphosphate is a weak inhibitor of human DNA polymerases α and γ with Ki values of 1.18 μM and 0.97μM, respectively.
AbsorptionThe approximate oral bioavailability of adefovir from HEPSERA is 59%. When a single oral 10 mg dose is given to chronic hepatitis B patients, the peak plasma concentration (Cmax) of adefovir was 18.4 ± 6.26 ng/mL. This occurred between 0.58 - 4 hours post dose (Tmax). The adefovir area under the plasma concentration-time curve (AUC0–∞) was 220 ± 70.0 ng∙h/mL. Food does not affect the exposure of adeforvir.
Volume of distribution
  • 392 ± 75 mL/kg [Vd at steady state, intravenous administration of 1.0 mg/kg/day]
  • 352 ± 9 mL/kg [Vd at steady state, intravenous administration of 3.0 mg/kg/day]
Protein binding≤4% over the adefovir concentration range of 0.1 to 25 μg/mL
Metabolism

Following oral administration, adefovir dipivoxil is rapidly converted to adefovir. 45% of the dose is recovered as adefovir in the urine over 24 hours at steady state following 10 mg oral doses. Adefovir is not a substrate of the cytochrome P450 enzymes.

SubstrateEnzymesProduct
Adefovir Dipivoxil
    AdefovirDetails
    Adefovir
    Adefovir monophosphateDetails
    Adefovir monophosphate
    Adefovir DiphosphateDetails
    Route of eliminationAdefovir is renally excreted by a combination of glomerular filtration and active tubular secretion.
    Half lifePlasma adefovir concentrations declined in a biexponential manner with a terminal elimination half-life of 7.48 ± 1.65 hours.
    Clearance
    • 469 ± 99.0 mL/min [Patients with Unimpaired renal Function receiving a 10 mg single dose]
    • 356 ± 85.6 mL/min [Patients with mild renal impairement receiving a 10 mg single dose]
    • 237 ± 118 mL/min [Patients with moderate renal impairement receiving a 10 mg single dose]
    • 91.7 ± 51.3 mL/min [Patients with severe renal impairement receiving a 10 mg single dose]
    ToxicityRenal tubular nephropathy characterized by histological alterations and/or increases in BUN and serum creatinine was the primary dose-limiting toxicity associated with administration of adefovir dipivoxil in animals. Nephrotoxicity was observed in animals at systemic exposures approximately 3–10 times higher than those in humans at the recommended therapeutic dose of 10 mg/day.
    Affected organisms
    • Hepatitis B virus
    Pathways
    PathwayCategorySMPDB ID
    Adefovir Dipivoxil Action PathwayDrug actionSMP00418
    Adefovir Dipivoxil Metabolism PathwayDrug metabolismSMP00629
    SNP Mediated EffectsNot Available
    SNP Mediated Adverse Drug ReactionsNot Available
    ADMET
    Predicted ADMET features
    Property Value Probability
    Human Intestinal Absorption + 0.9023
    Blood Brain Barrier + 0.8905
    Caco-2 permeable - 0.6281
    P-glycoprotein substrate Substrate 0.7113
    P-glycoprotein inhibitor I Non-inhibitor 0.5465
    P-glycoprotein inhibitor II Non-inhibitor 0.896
    Renal organic cation transporter Non-inhibitor 0.8273
    CYP450 2C9 substrate Non-substrate 0.9234
    CYP450 2D6 substrate Non-substrate 0.8305
    CYP450 3A4 substrate Substrate 0.5584
    CYP450 1A2 substrate Non-inhibitor 0.7508
    CYP450 2C9 substrate Non-inhibitor 0.725
    CYP450 2D6 substrate Non-inhibitor 0.7985
    CYP450 2C19 substrate Non-inhibitor 0.7005
    CYP450 3A4 substrate Non-inhibitor 0.7139
    CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8392
    Ames test Non AMES toxic 0.5535
    Carcinogenicity Non-carcinogens 0.828
    Biodegradation Not ready biodegradable 0.9762
    Rat acute toxicity 2.6261 LD50, mol/kg Not applicable
    hERG inhibition (predictor I) Weak inhibitor 0.6903
    hERG inhibition (predictor II) Non-inhibitor 0.7412
    Pharmacoeconomics
    Manufacturers
    • Gilead sciences inc
    Packagers
    Dosage forms
    FormRouteStrength
    TabletOral10 mg
    Prices
    Unit descriptionCostUnit
    Hepsera 10 mg tablet30.32USDtablet
    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
    Patents
    CountryPatent NumberApprovedExpires (estimated)
    United States64513401998-07-232018-07-23
    United States56631591994-09-022014-09-02
    Canada22980572008-11-182018-07-23
    Canada20512392003-03-252011-09-12
    Properties
    Statesolid
    Experimental Properties
    PropertyValueSource
    water solubility19 mg/mL at pH 2.0 and 0.4 mg/mL at pH 7.2.FDA label
    logP1.91FDA label
    Predicted Properties
    PropertyValueSource
    water solubility6.33e-01 g/lALOGPS
    logP1.49ALOGPS
    logP3.06ChemAxon
    logS-2.9ALOGPS
    pKa (strongest acidic)18.59ChemAxon
    pKa (strongest basic)5.13ChemAxon
    physiological charge0ChemAxon
    hydrogen acceptor count8ChemAxon
    hydrogen donor count1ChemAxon
    polar surface area166.98ChemAxon
    rotatable bond count15ChemAxon
    refractivity119.99ChemAxon
    polarizability49ChemAxon
    number of rings2ChemAxon
    bioavailability0ChemAxon
    rule of fiveNoChemAxon
    Ghose filterNoChemAxon
    Veber's ruleNoChemAxon
    MDDR-like ruleNoChemAxon
    Spectra
    SpectraNot Available
    References
    Synthesis Reference

    DrugSyn.org

    US4808716
    General Reference
    1. FDA label
    External Links
    ResourceLink
    KEGG DrugD01655
    KEGG CompoundC11277
    PubChem Compound60871
    PubChem Substance46507520
    ChemSpider54855
    BindingDB50038612
    Therapeutic Targets DatabaseDNC001135
    PharmGKBPA10005
    RxListhttp://www.rxlist.com/cgi/generic3/hepsera.htm
    Drugs.comhttp://www.drugs.com/cdi/adefovir.html
    WikipediaAdefovir
    ATC CodesJ05AF08
    AHFS Codes
    • 08:18.32
    PDB EntriesNot Available
    FDA labelshow(293 KB)
    MSDSshow(57 KB)
    Interactions
    Drug Interactions
    Drug
    ValganciclovirThe adverse/toxic effects of reverse transcriptase inhibitors (nucleoside), such as Adefovir Dipivoxil, may be enhanced by Valganciclovir. There is a risk of hematologic toxicity. Diligent monitoring during concomitant therapy is recommended.
    Food Interactions
    • Take without regard to meals.

    1. Protein P

    Kind: protein

    Organism: HBV-D

    Pharmacological action: yes

    Actions: other

    Components

    Name UniProt ID Details
    Protein P P24024 Details

    References:

    1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
    2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
    3. Chien RN, Liaw YF: Nucleos(t)ide analogues for hepatitis B virus: strategies for long-term success. Best Pract Res Clin Gastroenterol. 2008;22(6):1081-92. Pubmed
    4. Kock J, Baumert TF, Delaney WE 4th, Blum HE, von Weizsacker F: Inhibitory effect of adefovir and lamivudine on the initiation of hepatitis B virus infection in primary tupaia hepatocytes. Hepatology. 2003 Dec;38(6):1410-8. Pubmed

    1. Adenylate kinase 2, mitochondrial

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Adenylate kinase 2, mitochondrial P54819 Details

    References:

    1. https://www.pharmgkb.org/pathway/PA155028030

    2. Adenylate kinase 4, mitochondrial

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Adenylate kinase 4, mitochondrial P27144 Details

    References:

    1. https://www.pharmgkb.org/pathway/PA155028030

    3. Nucleoside diphosphate kinase A

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Nucleoside diphosphate kinase A P15531 Details

    References:

    1. https://www.pharmgkb.org/pathway/PA155028030

    4. Nucleoside diphosphate kinase B

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Nucleoside diphosphate kinase B P22392 Details

    References:

    1. https://www.pharmgkb.org/pathway/PA155028030

    1. Solute carrier family 22 member 6

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate inhibitor

    Components

    Name UniProt ID Details
    Solute carrier family 22 member 6 Q4U2R8 Details

    References:

    1. Cihlar T, Ho ES: Fluorescence-based assay for the interaction of small molecules with the human renal organic anion transporter 1. Anal Biochem. 2000 Jul 15;283(1):49-55. Pubmed
    2. Cihlar T, Lin DC, Pritchard JB, Fuller MD, Mendel DB, Sweet DH: The antiviral nucleotide analogs cidofovir and adefovir are novel substrates for human and rat renal organic anion transporter 1. Mol Pharmacol. 1999 Sep;56(3):570-80. Pubmed
    3. Ho ES, Lin DC, Mendel DB, Cihlar T: Cytotoxicity of antiviral nucleotides adefovir and cidofovir is induced by the expression of human renal organic anion transporter 1. J Am Soc Nephrol. 2000 Mar;11(3):383-93. Pubmed

    2. Multidrug resistance-associated protein 4

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Multidrug resistance-associated protein 4 O15439 Details

    References:

    1. Schuetz JD, Connelly MC, Sun D, Paibir SG, Flynn PM, Srinivas RV, Kumar A, Fridland A: MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nat Med. 1999 Sep;5(9):1048-51. Pubmed

    3. Multidrug resistance-associated protein 5

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Multidrug resistance-associated protein 5 O15440 Details

    References:

    1. Wijnholds J, Mol CA, van Deemter L, de Haas M, Scheffer GL, Baas F, Beijnen JH, Scheper RJ, Hatse S, De Clercq E, Balzarini J, Borst P: Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7476-81. Pubmed

    4. Solute carrier family 22 member 3

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Solute carrier family 22 member 3 O75751 Details

    References:

    1. Grundemann D, Schechinger B, Rappold GA, Schomig E: Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nat Neurosci. 1998 Sep;1(5):349-51. Pubmed

    5. Solute carrier family 22 member 8

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Solute carrier family 22 member 8 Q8TCC7 Details

    References:

    1. https://www.pharmgkb.org/pathway/PA155028030

    Comments
    Drug created on June 13, 2005 07:24 / Updated on October 08, 2013 14:21