You are using an unsupported browser. Please upgrade your browser to a newer version to get the best experience on DrugBank.
Identification
NameAbacavir
Accession NumberDB01048  (APRD00216)
TypeSmall Molecule
GroupsApproved, Investigational
Description

Abacavir (ABC) is a powerful nucleoside analog reverse transcriptase inhibitor (NRTI) used to treat HIV and AIDS. [Wikipedia] Chemically, it is a synthetic carbocyclic nucleoside and is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. In vivo, abacavir sulfate dissociates to its free base, abacavir.

Structure
Thumb
Synonyms
SynonymLanguageCode
{(1S-cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]cyclopent-2-en-1-yl}methanolNot AvailableNot Available
AbacavirNot AvailableNot Available
ABC Not AvailableNot Available
Salts
Name/CAS Structure Properties
Abacavir Sulfate
188062-50-2
Thumb
  • InChI Key: WMHSRBZIJNQHKT-WOIBLURINA-N
  • Monoisotopic Mass: 670.275797698
  • Average Mass: 670.743
DBSALT000871
Brand names
NameCompany
ZiagenViiV Healthcare Company
Brand mixtures
Brand NameIngredients
EpzicomAbacavir Sulfate + Lamivudine
KivexaAbacavir Sulfate + Lamivudine
TrizivirAbacavir Sulfate + Lamivudine + Zidovudine
Categories
CAS number136470-78-5
WeightAverage: 286.3323
Monoisotopic: 286.154209228
Chemical FormulaC14H18N6O
InChI KeyMCGSCOLBFJQGHM-SCZZXKLOSA-N
InChI
InChI=1S/C14H18N6O/c15-14-18-12(17-9-2-3-9)11-13(19-14)20(7-16-11)10-4-1-8(5-10)6-21/h1,4,7-10,21H,2-3,5-6H2,(H3,15,17,18,19)/t8-,10+/m1/s1
IUPAC Name
[(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]cyclopent-2-en-1-yl]methanol
SMILES
NC1=NC2=C(N=CN2[C@@H]2C[C@H](CO)C=C2)C(NC2CC2)=N1
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassOrganooxygen Compounds
ClassCarbohydrates and Carbohydrate Conjugates
SubclassGlycosyl Compounds
Direct parentPurine Nucleosides and Analogues
Alternative parentsPurines and Purine Derivatives; Aminopyrimidines and Derivatives; Primary Aromatic Amines; N-substituted Imidazoles; Cyclic Alcohols and Derivatives; Primary Alcohols; Polyamines; Secondary Amines
Substituentspurine; imidazopyrimidine; aminopyrimidine; n-substituted imidazole; primary aromatic amine; pyrimidine; cyclic alcohol; imidazole; azole; secondary amine; primary alcohol; polyamine; primary amine; alcohol; amine; organonitrogen compound
Classification descriptionThis compound belongs to the purine nucleosides and analogues. These are compounds comprising a purine base attached to a sugar.
Pharmacology
IndicationFor the treatment of HIV-1 infection, in combination with other antiretroviral agents.
PharmacodynamicsAbacavir is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Abacavir is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The concentration of drug necessary to effect viral replication by 50 percent (EC50) ranged from 3.7 to 5.8 μM (1 μM = 0.28 mcg/mL) and 0.07 to 1.0 μM against HIV-1IIIB and HIV-1BaL, respectively, and was 0.26 ± 0.18 μM against 8 clinical isolates. Abacavir had synergistic activity in cell culture in combination with the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine, the non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine, and the protease inhibitor (PI) amprenavir; and additive activity in combination with the NRTIs didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zalcitabine.
Mechanism of actionAbacavir is a carbocyclic synthetic nucleoside analogue and an antiviral agent. Intracellularly, abacavir is converted by cellular enzymes to the active metabolite carbovir triphosphate, an analogue of deoxyguanosine-5'-triphosphate (dGTP). Carbovir triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. Viral DNA growth is terminated because the incorporated nucleotide lacks a 3'-OH group, which is needed to form the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation.
AbsorptionRapid and extensive after oral administration (83% bioavailability, tablet). When a 300 mg tablet is given twice daily to subjects, the peak plasma concentration (Cmax) was 3.0 ± 0.89 mcg/mL and the area under the curve (AUC 0-12 hours) was 6.02 ± 1.73 mcg•hr/mL.
Volume of distribution
  • 0.86 ± 0.15 L/kg [IV administration]
Protein bindingModerate (approximately 50%). Binding of abacavir to plasma protein was independent of concentration.
Metabolism

Hepatic, by alcohol dehydrogenase and glucuronosyltransferase to a 5′-carboxylic acid metabolite and 5′-glucuronide metabolite, respectively. These metabolites have no antiviral activity. Abacavir is not significantly metabolized by cytochrome P450 enzymes.

Route of eliminationElimination of abacavir was quantified in a mass balance study following administration of a 600-mg dose of 14C-abacavir: 99% of the radioactivity was recovered, 1.2% was excreted in the urine as abacavir, 30% as the 5′-carboxylic acid metabolite, 36% as the 5′-glucuronide metabolite, and 15% as unidentified minor metabolites in the urine. Fecal elimination accounted for 16% of the dose. Renal excretion of unchanged abacavir is a minor route of elimination in humans.
Half life1.54 ± 0.63 hours
Clearance
  • 0.80 ± 0.24 L/hr/kg [asymptomatic, HIV-1-infected adult patients receiving single (IV dose of 150 mg]
ToxicitySome myocardial degeneration has been noticed in rats and mice. The most commonly reported adverse reactions of at least moderate intensity (incidence ≥10%) in adult HIV-1 clinical trials were nausea, headache, malaise and fatigue, nausea and vomiting, and dreams/sleep disorders. Serious hypersensitivity reactions have been associated with abacavir which has been strongly linked to the presence of the HLA-B*57:01 allele. This reaction manifests itself in patients within the first 6 weeks of treatment. Patients should be tested for the presence of this allele as recommended by the U.S Food and Drug Administration (FDA).
Affected organisms
  • Human Immunodeficiency Virus
Pathways
PathwayCategorySMPDB ID
Abacavir Action PathwayDrug actionSMP00737
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug Reactions
Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeAdverse ReactionReference(s)
HLA class I histocompatibility antigen protein P5
Gene symbol: HCP5
UniProt: Q6MZN7
rs2395029 HLA-B*5701G allelePresence of this SNP is predicative of hypersenitivity reaction when abacavir is given to HIV+ patients.18684101
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 1.0
Blood Brain Barrier + 0.9383
Caco-2 permeable - 0.5808
P-glycoprotein substrate Non-substrate 0.5551
P-glycoprotein inhibitor I Non-inhibitor 0.9155
P-glycoprotein inhibitor II Non-inhibitor 0.6573
Renal organic cation transporter Non-inhibitor 0.7734
CYP450 2C9 substrate Non-substrate 0.8595
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Non-substrate 0.7376
CYP450 1A2 substrate Non-inhibitor 0.538
CYP450 2C9 substrate Non-inhibitor 0.8707
CYP450 2D6 substrate Non-inhibitor 0.7852
CYP450 2C19 substrate Non-inhibitor 0.8667
CYP450 3A4 substrate Non-inhibitor 0.559
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8683
Ames test Non AMES toxic 0.6662
Carcinogenicity Non-carcinogens 0.8649
Biodegradation Not ready biodegradable 0.9806
Rat acute toxicity 2.4758 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.8918
hERG inhibition (predictor II) Non-inhibitor 0.8734
Pharmacoeconomics
Manufacturers
  • Viiv healthcare co
Packagers
Dosage forms
FormRouteStrength
SolutionOral20 mg/mL
TabletOral300 mg
Prices
Unit descriptionCostUnit
Epzicom tablet35.78USDtablet
Ziagen 300 mg tablet10.46USDtablet
Ziagen 20 mg/ml Solution0.7USDml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States66418432000-02-042020-02-04
United States50895001992-12-262009-12-26
Canada22897532007-01-232018-05-14
Canada13405891999-06-082016-06-08
Canada22166342004-07-202016-03-28
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point165 °CNot Available
water solubility77 mg/mL (sulfate salt)FDA label
logP1.20 FDA label
Predicted Properties
PropertyValueSource
Water Solubility1.21ALOGPS
logP0.61ALOGPS
logP0.39ChemAxon
logS-2.4ALOGPS
pKa (Strongest Acidic)15.41ChemAxon
pKa (Strongest Basic)5.77ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area101.88 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity82.62 m3·mol-1ChemAxon
Polarizability30.43 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

DrugSyn.org

US5034394
General Reference
  1. Zucman D, Truchis P, Majerholc C, Stegman S, Caillat-Zucman S: Prospective screening for human leukocyte antigen-B*5701 avoids abacavir hypersensitivity reaction in the ethnically mixed French HIV population. J Acquir Immune Defic Syndr. 2007 May 1;45(1):1-3. Pubmed
  2. FDA label
  3. http://pharmgkb.org/pathway/PA166104634#
External Links
ResourceLink
KEGG DrugD07057
KEGG CompoundC07624
PubChem Compound441300
PubChem Substance46505718
ChemSpider58649
ChEBI2360
ChEMBLCHEMBL1380
Therapeutic Targets DatabaseDAP000704
PharmGKBPA448004
Drug Product Database2240358
RxListhttp://www.rxlist.com/cgi/generic/abavir.htm
Drugs.comhttp://www.drugs.com/cdi/abacavir.html
PDRhealthhttp://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/cx1527.shtml
WikipediaAbacavir
ATC CodesJ05AF06
AHFS Codes
  • 08:18.08.20
PDB EntriesNot Available
FDA labelshow(118 KB)
MSDSshow(34.7 KB)
Interactions
Drug Interactions
Drug
AmprenavirThe serum concentration of Abacavir may be decreased by protease inhibitors such as Amprenavir. The antiviral response should be closely monitored.
AtazanavirThe serum concentration of Abacavir may be decreased by protease inhibitors such as Atazanavir. The antiviral response should be closely monitored.
DarunavirThe serum concentration of Abacavir may be decreased by protease inhibitors such as Darunavir. The antiviral response should be closely monitored.
EthanolAbacavir is partly metabolized through the alcohol dehydrogenase enzyme system. Alcohol increases the area under the curve (about 41%) of Abacavir. Interaction does not appear to be clinically significant.
FosamprenavirThe serum concentration of Abacavir may be decreased by protease inhibitors such as Fosamprenavir. The antiviral response should be closely monitored.
GanciclovirThe adverse/toxic effects of reverse transcriptase inhibitors (nucleoside), such as Abacavir, may be enhanced by Ganciclovir. There is a risk of hematologic toxicity. Diligent monitoring during concomitant therapy is required.
IndinavirThe serum concentration of Abacavir may be decreased by protease inhibitors such as Indinavir. The antiviral response should be closely monitored.
LopinavirThe serum concentration of Abacavir may be decreased by protease inhibitors such as Lopinavir. The antiviral response should be closely monitored.
NelfinavirThe serum concentration of Abacavir may be decreased by protease inhibitors such as Nelfinavir. The antiviral response should be closely monitored.
RibavirinRibavirin may increase the hepatotoxicity of reverse transcriptase inhibitors (nucleoside) such as Abacavir. Lactic acidosis may occur. Consider modifying therapy.
Ribavirin MonophosphateRibavirin Monophosphate may increase the hepatotoxicity of reverse transcriptase inhibitors (nucleoside) such as Abacavir. Lactic acidosis may occur. Consider modifying therapy.
RitonavirThe serum concentration of Abacavir may be decreased by protease inhibitors such as Ritonavir. The antiviral response should be closely monitored.
SaquinavirThe serum concentration of Abacavir may be decreased by protease inhibitors such as Saquinavir. The antiviral response should be closely monitored.
TipranavirThe serum concentration of Abacavir may be decreased by protease inhibitors such as Tipranavir. The antiviral response should be closely monitored.
ValganciclovirThe adverse/toxic effects of reverse transcriptase inhibitors (nucleoside), such as Abacavir, may be enhanced by Valganciclovir. There is a risk of hematologic toxicity. Diligent monitoring during concomitant therapy is recommended.
Food Interactions
  • Abacavir is partly metabolised through the alcohol-dehydrogenase enzyme system.
  • Alcohol significantly increases abacavir's area under the curve (about 41%).
  • Avoid alcohol.
  • Take without regard to meals.

Targets

1. Reverse Transcriptase

Kind: protein

Organism: Human immunodeficiency virus 1

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Reverse transcriptase/RNaseH Q72547 Details

References:

  1. De Clercq E: New anti-HIV agents and targets. Med Res Rev. 2002 Nov;22(6):531-65. Pubmed
  1. Faletto MB, Miller WH, Garvey EP, St Clair MH, Daluge SM, Good SS: Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89. Antimicrob Agents Chemother. 1997 May;41(5):1099-107. Pubmed
  2. Crimmins MT, King BW: An Efficient Asymmetric Approach to Carbocyclic Nucleosides: Asymmetric Synthesis of 1592U89, a Potent Inhibitor of HIV Reverse Transcriptase. J Org Chem. 1996 Jun 26;61(13):4192-4193. Pubmed

Enzymes

1. Alcohol dehydrogenase 6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Alcohol dehydrogenase 6 P28332 Details

References:

  1. Yuen GJ, Weller S, Pakes GE: A review of the pharmacokinetics of abacavir. Clin Pharmacokinet. 2008;47(6):351-71. Pubmed

2. UDP-glucuronosyltransferase 1-1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
UDP-glucuronosyltransferase 1-1 P22309 Details

References:

  1. Yuen GJ, Weller S, Pakes GE: A review of the pharmacokinetics of abacavir. Clin Pharmacokinet. 2008;47(6):351-71. Pubmed

3. Adenosine kinase

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Adenosine kinase P55263 Details

References:

  1. Faletto MB, Miller WH, Garvey EP, St Clair MH, Daluge SM, Good SS: Unique intracellular activation of the potent anti-human immunodeficiency virus agent 1592U89. Antimicrob Agents Chemother. 1997 May;41(5):1099-107. Pubmed

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