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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 dipivoxilNot AvailableNot Available
Adefovir PivoxilNot AvailableJAN
AdefovirumLatinINN
HePSeraNot AvailableNot Available
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 KeyWOZSCQDILHKSGG-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
Not Available
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 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 Solubility0.633ALOGPS
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 Area166.98 Å2ChemAxon
Rotatable Bond Count15ChemAxon
Refractivity119.99 m3·mol-1ChemAxon
Polarizability49 Å3ChemAxon
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.

Targets

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

Enzymes

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

Transporters

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

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