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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
Adéfovir
Adefovir
Adefovir dipivoxil
Adefovir Pivoxil
Adefovirum
HePSera
External Identifiers
  • Bis (pom) PMEA
  • GS 0393
  • GS 0840
  • Piv2 PMEA
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Hepseratablet10 mg/1oralExcella Gmb H2002-09-20Not applicableUs
Hepseratablet10 mgoralGilead Sciences Canada Inc2006-04-18Not applicableCanada
Hepseratablet10 mg/1oralGilead Sciences, Inc.2002-09-20Not applicableUs
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Adefovir Dipivoxiltablet10 mg/1oralSigmapharm Laboratories, LLC2013-09-03Not applicableUs
Apo-adefovirtablet10 mgoralApotex Inc2014-08-07Not applicableCanada
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
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
InfovirIncepta
JiuleFovir Pharm
LifuzhiJiangsu TianShiLi BeiTe Pharmaceutical Co., Ltd.
Ming ZhengChia Tai Tianqing
NafaseraVidipha
PreveonGilead Sciences, Inc.
PymefovirPMP
XinfunuoSL Pharm
YilaifenQilu
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIU6Q8Z01514
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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as 6-aminopurines. These are purines that carry an amino group at position 6. Purine is a bicyclic aromatic compound made up of a pyrimidine ring fused to an imidazole ring.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassImidazopyrimidines
Sub ClassPurines and purine derivatives
Direct Parent6-aminopurines
Alternative Parents
Substituents
  • 6-aminopurine
  • Phosphonic acid diester
  • Aminopyrimidine
  • Imidolactam
  • Pyrimidine
  • Primary aromatic amine
  • Phosphonic acid ester
  • N-substituted imidazole
  • Dicarboxylic acid or derivatives
  • Heteroaromatic compound
  • Organophosphonic acid derivative
  • Imidazole
  • Azole
  • Carboxylic acid ester
  • Azacycle
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Primary amine
  • Organophosphorus compound
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External DescriptorsNot Available
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.
Related Articles
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
PropertyValueProbability
Human Intestinal Absorption+0.9023
Blood Brain Barrier+0.8905
Caco-2 permeable-0.6281
P-glycoprotein substrateSubstrate0.7113
P-glycoprotein inhibitor INon-inhibitor0.5465
P-glycoprotein inhibitor IINon-inhibitor0.896
Renal organic cation transporterNon-inhibitor0.8273
CYP450 2C9 substrateNon-substrate0.9234
CYP450 2D6 substrateNon-substrate0.8305
CYP450 3A4 substrateSubstrate0.5584
CYP450 1A2 substrateNon-inhibitor0.7508
CYP450 2C9 inhibitorNon-inhibitor0.725
CYP450 2D6 inhibitorNon-inhibitor0.7985
CYP450 2C19 inhibitorNon-inhibitor0.7005
CYP450 3A4 inhibitorNon-inhibitor0.7139
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8392
Ames testNon AMES toxic0.5535
CarcinogenicityNon-carcinogens0.828
BiodegradationNot ready biodegradable0.9762
Rat acute toxicity2.6261 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6903
hERG inhibition (predictor II)Non-inhibitor0.7412
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Gilead sciences inc
Packagers
Dosage forms
FormRouteStrength
Tabletoral10 mg/1
Tabletoral10 mg
Prices
Unit descriptionCostUnit
Hepsera 10 mg tablet30.32USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA2051239 No2003-03-252011-09-12Canada
CA2298057 No2008-11-182018-07-23Canada
US5663159 No1994-09-022014-09-02Us
US6451340 No1998-07-232018-07-23Us
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 Solubility0.633 mg/mLALOGPS
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 FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

DrugSyn.org

US4808716
General ReferencesNot Available
External Links
ATC CodesJ05AF08
AHFS Codes
  • 08:18.32
PDB EntriesNot Available
FDA labelDownload (293 KB)
MSDSDownload (57 KB)
Interactions
Drug Interactions
Drug
GanciclovirThe risk or severity of adverse effects can be increased when Ganciclovir is combined with Adefovir Dipivoxil.
RibavirinRibavirin may increase the hepatotoxic activities of Adefovir Dipivoxil.
TenofovirThe therapeutic efficacy of Tenofovir can be decreased when used in combination with Adefovir Dipivoxil.
Food Interactions
  • Take without regard to meals.

Targets

Kind
Protein
Organism
HBV-D
Pharmacological action
yes
Actions
other
General Function:
Rna-dna hybrid ribonuclease activity
Specific Function:
Multifunctional enzyme that converts the viral RNA genome into dsDNA in viral cytoplasmic capsids. This enzyme displays a DNA polymerase activity that can copy either DNA or RNA templates, and a ribonuclease H (RNase H) activity that cleaves the RNA strand of RNA-DNA heteroduplexes in a partially processive 3'- to 5'-endonucleasic mode. Neo-synthesized pregenomic RNA (pgRNA) are encapsidated to...
Gene Name:
P
Uniprot ID:
P24024
Molecular Weight:
93588.765 Da
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:17139284 ]
  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:17016423 ]
  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. doi: 10.1016/j.bpg.2008.11.003. [PubMed:19187868 ]
  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:14647052 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Atp binding
Specific Function:
Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP. Plays an important role in cellular energy homeostasis and in adenine nucleotide metabolism. Adenylate kinase activity is critical for regulation of the phosphate utilization and the AMP de novo biosynthesis pathways. Plays a key role in hematopoiesis.
Gene Name:
AK2
Uniprot ID:
P54819
Molecular Weight:
26477.44 Da
References
  1. Link [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Nucleoside triphosphate adenylate kinase activity
Specific Function:
Involved in maintaining the homeostasis of cellular nucleotides by catalyzing the interconversion of nucleoside phosphates. Efficiently phosphorylates AMP and dAMP using ATP as phosphate donor, but phosphorylates only AMP when using GTP as phosphate donor. Also displays broad nucleoside diphosphate kinase activity.
Gene Name:
AK4
Uniprot ID:
P27144
Molecular Weight:
25267.83 Da
References
  1. Link [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Ribosomal small subunit binding
Specific Function:
Major role in the synthesis of nucleoside triphosphates other than ATP. The ATP gamma phosphate is transferred to the NDP beta phosphate via a ping-pong mechanism, using a phosphorylated active-site intermediate. Possesses nucleoside-diphosphate kinase, serine/threonine-specific protein kinase, geranyl and farnesyl pyrophosphate kinase, histidine protein kinase and 3'-5' exonuclease activities....
Gene Name:
NME1
Uniprot ID:
P15531
Molecular Weight:
17148.635 Da
References
  1. Link [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Transcription factor activity, sequence-specific dna binding
Specific Function:
Major role in the synthesis of nucleoside triphosphates other than ATP. Negatively regulates Rho activity by interacting with AKAP13/LBC. Acts as a transcriptional activator of the MYC gene; binds DNA non-specifically (PubMed:8392752). Exhibits histidine protein kinase activity.
Gene Name:
NME2
Uniprot ID:
P22392
Molecular Weight:
17297.935 Da
References
  1. Link [Link]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one molecule of endogenous dicarboxylic acid (glutarate, ketoglutarate, etc). Mediates the sodium-independent uptake of 2,3-dimercapto-1-propanesulfonic acid (DMPS) (By similarity). Mediates the sodium-in...
Gene Name:
SLC22A6
Uniprot ID:
Q4U2R8
Molecular Weight:
61815.78 Da
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:10929807 ]
  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:10462545 ]
  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:10703662 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Atpase activity, coupled to transmembrane movement of substances
Specific Function:
May be an organic anion pump relevant to cellular detoxification.
Gene Name:
ABCC4
Uniprot ID:
O15439
Molecular Weight:
149525.33 Da
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:10470083 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Organic anion transmembrane transporter activity
Specific Function:
Acts as a multispecific organic anion pump which can transport nucleotide analogs.
Gene Name:
ABCC5
Uniprot ID:
O15440
Molecular Weight:
160658.8 Da
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:10840050 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Toxin transporter activity
Specific Function:
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.
Gene Name:
SLC22A3
Uniprot ID:
O75751
Molecular Weight:
61279.485 Da
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:10196521 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Plays an important role in the excretion/detoxification of endogenous and exogenous organic anions, especially from the brain and kidney. Involved in the transport basolateral of steviol, fexofenadine. Transports benzylpenicillin (PCG), estrone-3-sulfate (E1S), cimetidine (CMD), 2,4-dichloro-phenoxyacetate (2,4-D), p-amino-hippurate (PAH), acyclovir (ACV) and ochratoxin (OTA).
Gene Name:
SLC22A8
Uniprot ID:
Q8TCC7
Molecular Weight:
59855.585 Da
References
  1. Link [Link]
Comments
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Drug created on June 13, 2005 07:24 / Updated on June 27, 2016 01:52