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targets (1) transporters (4)
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Identification
Name Adefovir Dipivoxil
Accession Number DB00718 (APRD00781)
Type small molecule
Groups approved
Description

Adefovir dipivoxil, previously called bis-POM PMEA, with trade names Preveon and Hepsera, is an orally-administered nucleotide analog reverse transcriptase inhibitor (ntRTI) used for treatment of hepatitis B. It is a failed treatment for HIV. [Wikipedia]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Adefovir
  • adefovir dipivoxil
  • Adefovir pivoxil
  • Adefovirdipivoxl
  • ADV
  • bis-POM PMEA
  • GS-840
  • PMEA
Brand names
  • Hepsera
  • Preveon
Brand name mixtures Not Available
Categories
  • Antiviral Agents
  • Reverse Transcriptase Inhibitors
CAS number 142340-99-6
Weight Average: 501.4705
Monoisotopic: 501.198849537
Chemical Formula C20H32N5O8P
InChI Key InChIKey=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)
Plain Text
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=C1N=CN=C2N)OCOC(=O)C(C)(C)C
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Purines and Purine Derivatives
Substructures
  • Carbonyl Compounds
  • Carboxylic Acids and Derivatives
  • Acetates
  • Phosphonic Acids and Derivatives
  • Aliphatic and Aryl Amines
  • Ethers
  • Pyrimidines and Derivatives
  • Imidazoles
  • Heterocyclic compounds
  • Aromatic compounds
  • Purines and Purine Derivatives
  • Phosphinic Acids and Derivatives
  • Cyanamides
Pharmacology
Indication For 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.
Pharmacodynamics Adefovir 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 action Adefovir 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.
Absorption Approximate oral bioavailability is 59%.
Volume of distribution
  • 392 ± 75 mL/kg [intravenous administration of 1.0 mg/kg/day]
  • 352 ± 9 mL/kg [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. Forty-five percent 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.
Route of elimination Adefovir is renally excreted by a combination of glomerular filtration and active tubular secretion.
Half life 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]
Toxicity Renal 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
Pathway Name SMPDB ID
Smp00418 Adefovir Dipivoxil Pathway SMP00418
Pharmacoeconomics
Manufacturers
  • Gilead sciences inc
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Hepsera 10 mg tablet 30.32 USD tablet
Patents
Country Patent Number Approved Expires
United States 6451340 1998-07-23 2018-07-23
United States 5663159 1994-09-02 2014-09-02
Canada 2298057 2008-11-18 2018-07-23
Canada 2051239 2003-03-25 2011-09-12
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
water solubility 19 mg/mL at pH 2.0 and 0.4 mg/mL at pH 7.2. PhysProp
logP 0.8 PhysProp
Predicted Properties
Property Value Source
water solubility 6.33e-01 g/l ALOGPS
logP 1.49 ALOGPS
logP 3.06 ChemAxon Molconvert
logS -2.90 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 8 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 166.98 ChemAxon Molconvert
rotatable bond count 15 ChemAxon Molconvert
refractivity 119.99 ChemAxon Molconvert
polarizability 49.00 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference Not Available
External Links
Resource Link
KEGG Drug D01655 Link_out
PubChem Compound 60871 Link_out
PubChem Substance 46507520 Link_out
ChemSpider 54855 Link_out
BindingDB 50038612 Link_out
Therapeutic Targets Database DNC001135 Link_out
Drug Product Database 0 Link_out
RxList http://www.rxlist.com/cgi/generic3/hepsera.htm Link_out
Drugs.com http://www.drugs.com/cdi/adefovir.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Adefovir Link_out
ATC Codes
  • J05AF08
AHFS Codes
  • 08:18.32
PDB Entries Not Available
FDA label show (293.3 KB)
MSDS show (57 KB)
Interactions
Drug Interactions Not Available
Food Interactions
  • Take without regard to meals.
Targets

1. P protein [Includes: DNA-directed DNA polymerase

Pharmacological action: yes
Actions: other
Organism class: viral
UniProt ID: P24024 Link_out
Gene: P
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Transporters

1. Solute carrier family 22 member 6

Actions: substrate, inhibitor
UniProt ID: Q4U2R8 Link_out
Gene: hROAT1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

May be an organic anion pump relevant to cellular detoxification

UniProt ID: O15439 Link_out
Gene: ABCC4 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Acts as a multispecific organic anion pump which can transport nucleotide analogs

UniProt ID: O15440 Link_out
Gene: ABCC5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Mediates potential-dependent transport of a variety of organic cations. May play a significant role in the disposition of cationic neurotoxins and neurotransmitters in the brain

UniProt ID: O75751 Link_out
Gene: SLC22A3 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:42

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.