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Identification
NameAciclovir
Accession NumberDB00787  (APRD00567, EXPT00406)
Typesmall molecule
Groupsapproved
Description

A guanosine analog antiviral drug that acts as an antimetabolite. Aciclovir is used for the treatment of herpes simplex virus infections, varicella zoster (chickenpox) and herpes zoster (shingles).

Structure
Thumb
Synonyms
SynonymLanguageCode
AcycloguanosineNot AvailableNot Available
AcyclovirNot AvailableUSAN
Salts
Name/CAS Structure Properties
Aciclovir Sodium
69657-51-8
Thumb
  • InChI Key:
  • Monoisotopic Mass:
  • Average Mass:
DBSALT000004
Brand names
NameCompany
SitavigBioalliance Pharma SA
ZovirNot Available
ZoviraxNot Available
Brand mixtures
Brand NameIngredients
XereseAcyclovir 5% and hydrocortisone 1%
Categories
CAS number59277-89-3
WeightAverage: 225.2046
Monoisotopic: 225.086189243
Chemical FormulaC8H11N5O3
InChI KeyInChIKey=MKUXAQIIEYXACX-UHFFFAOYSA-N
InChI
InChI=1S/C8H11N5O3/c9-8-11-6-5(7(15)12-8)10-3-13(6)4-16-2-1-14/h3,14H,1-2,4H2,(H3,9,11,12,15)
IUPAC Name
2-amino-9-[(2-hydroxyethoxy)methyl]-6,9-dihydro-3H-purin-6-one
SMILES
NC1=NC(=O)C2=C(N1)N(COCCO)C=N2
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassHeterocyclic Compounds
ClassImidazopyrimidines
SubclassPurines and Purine Derivatives
Direct parentHypoxanthines
Alternative parentsPyrimidones; Primary Aromatic Amines; N-substituted Imidazoles; Primary Alcohols; Polyamines; Ethers
Substituentspyrimidone; n-substituted imidazole; pyrimidine; primary aromatic amine; imidazole; azole; ether; primary alcohol; polyamine; amine; primary amine; alcohol; organonitrogen compound
Classification descriptionThis compound belongs to the hypoxanthines. These are compounds containing the purine derivative 1H-purin-6(9H)-one.
Pharmacology
IndicationFor the treatment and management of herpes zoster (shingles), genital herpes, and chickenpox.
PharmacodynamicsAciclovir (INN) or acyclovir (USAN, former BAN) is a synthetic deoxyguanosine analog and it is the prototype antiviral agent that is activated by viral thymidine kinase. The selective activity of aciclovir is due to its affinity for the thymidine kinase enzyme encoded by HSV and VZV. EC50 value of acyclovir against clinical herpes virus isolates was 1.3 μM (range: < 0.56 to 3.3 μM).
Mechanism of actionViral (HSV-1, HSV-2 and VZV) thymidine kinase converts aciclovir to the aciclovir monophosphate, which is then converted to the diphosphate by cellular guanylate kinase, and finally to the triphosphate by phosphoglycerate kinase, phosphoenolpyruvate carboxykinase, and pyruvate kinase. Aciclovir triphosphate competitively inhibits viral DNA polymerase and competes with the natural deoxyguanosine triphosphate, for incorporation into viral DNA. Once incorporated, aciclovir triphosphate inhibits DNA synthesis by acting as a chain terminator. One may consider aciclovir to be a prodrug as it is metabolized to more active compounds. Aciclovir is selective and low in cytotoxicity as the cellular thymidine kinase of normal, uninfected cells does not use aciclovir effectively as a substrate.
AbsorptionThe oral bioavailability is 10% to 20%, and decreases with increasing dose. Food does not affect the absorption of acyclovir. The following are the pharmacokinetic parameters for 50 mg buccal tablet, Sitavig, in the saliva: AUC 0 - 24 hours = 2900±2400 mcg.h/mL; Cmax = 440±241 mcg/mL; Tmax = 7.95 ± 4.08 hours.
Volume of distributionNot Available
Protein binding9%-33%
Metabolism

Hepatic, Acyclovir is metabolized to 9-[(carboxymethoxy)methyl]guanine (CMMG) and 8­ hydroxy-acyclovir (8-OH-ACV) by oxidation and hydroxylation. It is suggested in studies that acyclovir is first metabolized to acyclovir aldehyde by alcohol dehydrogenase and then converted to CMMG. The build up of acyclovir aldehyde may be the cause of acyclovir-induced nephrotoxicity in the absence of crystalluria.

SubstrateEnzymesProduct
Aciclovir
    9-carboxymethoxymethylguanineDetails
    Route of eliminationPrimarily excreted unchanged by the kidneys via active tubular secretion.
    Half life2.5-3.3 hours
    ClearanceNot Available
    ToxicityAciclovir may cause nephrotoxicity (crystallization of aciclovir within renal tubules, elevation of serum creatinine, transient), and neurotoxicity (coma, hallucinations, lethargy, seizures, tremors). Nephrotoxicity and neurotoxicity usually resolve after cessation of aciclovir therapy. However, there is no well-defined relationship between aciclovir concentrations in the blood and these adverse effects.
    Affected organisms
    • Human Herpes Virus
    PathwaysNot Available
    SNP Mediated EffectsNot Available
    SNP Mediated Adverse Drug ReactionsNot Available
    ADMET
    Predicted ADMET features
    Property Value Probability
    Human Intestinal Absorption Not Available Not Available
    Blood Brain Barrier Not Available Not Available
    Caco-2 permeable Not Available Not Available
    P-glycoprotein substrate Not Available Not Available
    P-glycoprotein inhibitor I Not Available Not Available
    P-glycoprotein inhibitor II Not Available Not Available
    Renal organic cation transporter Not Available Not Available
    CYP450 2C9 substrate Not Available Not Available
    CYP450 2D6 substrate Not Available Not Available
    CYP450 3A4 substrate Not Available Not Available
    CYP450 1A2 substrate Not Available Not Available
    CYP450 2C9 substrate Not Available Not Available
    CYP450 2D6 substrate Not Available Not Available
    CYP450 2C19 substrate Not Available Not Available
    CYP450 3A4 substrate Not Available Not Available
    CYP450 inhibitory promiscuity Not Available Not Available
    Ames test Not Available Not Available
    Carcinogenicity Not Available Not Available
    Biodegradation Not Available Not Available
    Rat acute toxicity Not Available Not applicable
    hERG inhibition (predictor I) Not Available Not Available
    hERG inhibition (predictor II) Not Available Not Available
    Pharmacoeconomics
    Manufacturers
    • Actavis elizabeth llc
    • Apotex inc etobicoke site
    • Belcher pharmaceuticals inc
    • Dava pharmaceuticals inc
    • Genpharm inc
    • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
    • Lek pharmaceutical and chemical co dd
    • Mylan pharmaceuticals inc
    • Ranbaxy laboratories ltd
    • Roxane laboratories inc
    • Stason industrial corp
    • Teva pharmaceuticals usa inc
    • Teva pharmaceuticals usa
    • Watson laboratories inc
    • Glaxosmithkline
    • Actavis mid atlantic llc
    • Hi tech pharmacal co inc
    • Carlsbad technology inc
    • Mylan laboratories inc
    • Abbott laboratories
    • Baxter healthcare corp anesthesia and critical care
    • Apothecon inc div bristol myers squibb
    • App pharmaceuticals llc
    • Bedford laboratories div ben venue laboratories inc
    • Hospira inc
    • Teva parenteral medicines inc
    Packagers
    Dosage forms
    FormRouteStrength
    CapsuleOral200 mg
    CreamTopical5%
    OintmentTopical5%
    SolutionIntravenous50 mg/mL
    SolutionIntravenous500 mg, 1000 mg
    SuspensionOral200 mg/5 mL
    TabletBuccal50 mg
    TabletOral400 mg, 800 mg
    Prices
    Unit descriptionCostUnit
    Zovirax 200 mg/5ml Suspension 473ml Bottle264.95USDbottle
    Zovirax 5% Ointment 15 gm Tube191.56USDtube
    Zovirax 5% Cream 5 gm Tube165.07USDtube
    Zovirax 5% Cream 2 gm Tube69.44USDtube
    Zovirax 5% cream30.22USDg
    Zovirax 800 mg tablet11.83USDtablet
    Zovirax 400 mg tablet6.09USDtablet
    Zovirax 800 mg Tablet5.71USDtablet
    Acyclovir 800 mg tablet3.81USDtablet
    Zovirax 200 mg capsule3.08USDcapsule
    Acyclovir 800 mg Tablet2.99USDtablet
    Apo-Acyclovir 800 mg Tablet2.99USDtablet
    Mylan-Acyclovir 800 mg Tablet2.99USDtablet
    Novo-Acyclovir 800 mg Tablet2.99USDtablet
    Nu-Acyclovir 800 mg Tablet2.99USDtablet
    Ratio-Acyclovir 800 mg Tablet2.99USDtablet
    Zovirax 400 mg Tablet2.9USDtablet
    Acyclovir 400 mg tablet2.26USDtablet
    Acyclovir 400 mg Tablet1.63USDtablet
    Apo-Acyclovir 400 mg Tablet1.63USDtablet
    Mylan-Acyclovir 400 mg Tablet1.63USDtablet
    Novo-Acyclovir 400 mg Tablet1.63USDtablet
    Nu-Acyclovir 400 mg Tablet1.63USDtablet
    Ratio-Acyclovir 400 mg Tablet1.63USDtablet
    Zovirax 200 mg Tablet1.44USDtablet
    Acyclovir 200 mg capsule1.01USDcapsule
    Acyclovir 200 mg Tablet0.81USDtablet
    Apo-Acyclovir 200 mg Tablet0.81USDtablet
    Mylan-Acyclovir 200 mg Tablet0.81USDtablet
    Novo-Acyclovir 200 mg Tablet0.81USDtablet
    Ratio-Acyclovir 200 mg Tablet0.81USDtablet
    Acyclovir 200 mg/5ml Suspension0.3USDml
    Zovirax 40 mg/ml Suspension0.28USDml
    DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
    Patents
    CountryPatent NumberApprovedExpires (estimated)
    Canada20981082001-07-032012-01-29
    Properties
    Statesolid
    Experimental Properties
    PropertyValueSource
    melting point255 °CPhysProp
    water solubility2.5 mg/mL at 37°CFDA label
    logP-1.56KRISTL,A ET AL. (1993)
    Caco2 permeability-6.15ADME Research, USCD
    pKa2.27 and 9.25 FDA label
    Predicted Properties
    PropertyValueSource
    water solubility9.08e+00 g/lALOGPS
    logP-0.95ALOGPS
    logP-1ChemAxon
    logS-1.4ALOGPS
    pKa (strongest acidic)7.99ChemAxon
    pKa (strongest basic)2.63ChemAxon
    physiological charge0ChemAxon
    hydrogen acceptor count7ChemAxon
    hydrogen donor count3ChemAxon
    polar surface area114.76ChemAxon
    rotatable bond count4ChemAxon
    refractivity54.63ChemAxon
    polarizability21.51ChemAxon
    number of rings2ChemAxon
    bioavailability1ChemAxon
    rule of fiveYesChemAxon
    Ghose filterNoChemAxon
    Veber's ruleNoChemAxon
    MDDR-like ruleNoChemAxon
    Spectra
    SpectraNot Available
    References
    Synthesis Reference

    DrugSyn.org

    US4294831
    General Reference
    1. O’Brien JJ, Campoli-Richards DM: Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. Drugs. 1989 Mar;37(3):233-309. Pubmed
    2. Gunness P, Aleksa K, Bend J, Koren G: Acyclovir-induced nephrotoxicity: the role of the acyclovir aldehyde metabolite. Transl Res. 2011 Nov;158(5):290-301. doi: 10.1016/j.trsl.2011.07.002. Epub 2011 Aug 3. Pubmed
    External Links
    ResourceLink
    KEGG DrugD00222
    KEGG CompoundC06810
    PubChem Compound2022
    PubChem Substance46506002
    ChemSpider1945
    ChEBI2453
    ChEMBLCHEMBL184
    Therapeutic Targets DatabaseDNC000157
    PharmGKBPA448045
    HETAC2
    Drug Product Database2242784
    RxListhttp://www.rxlist.com/cgi/generic/acyclo.htm
    Drugs.comhttp://www.drugs.com/acyclovir.html
    WikipediaAciclovir
    ATC CodesD06BB03J05AB01S01AD03
    AHFS Codes
    • 84:04.06
    • 08:18.32
    PDB Entries
    FDA labelNot Available
    MSDSshow(37 KB)
    Interactions
    Drug Interactions
    Drug
    AminophyllineAcyclovir increases the effect and toxicity of theophylline
    DyphyllineAcyclovir increases the effect and toxicity of dyphylline.
    OxtriphyllineAciclovir may increase the effect and toxicity of oxtriphylline.
    TheophyllineAcyclovir may increase the effect and toxicity of theophylline.
    Food Interactions
    • Increase liquid intake.
    • Take without regard to meals.

    1. Thymidine kinase

    Kind: protein

    Organism: HHV-1

    Pharmacological action: yes

    Actions: potentiator

    Components

    Name UniProt ID Details
    Thymidine kinase P03176 Details

    References:

    1. Bennett MS, Wien F, Champness JN, Batuwangala T, Rutherford T, Summers WC, Sun H, Wright G, Sanderson MR: Structure to 1.9 A resolution of a complex with herpes simplex virus type-1 thymidine kinase of a novel, non-substrate inhibitor: X-ray crystallographic comparison with binding of aciclovir. FEBS Lett. 1999 Jan 25;443(2):121-5. Pubmed

    2. DNA polymerase catalytic subunit

    Kind: protein

    Organism: HHV-1

    Pharmacological action: yes

    Actions: inhibitor

    Components

    Name UniProt ID Details
    DNA polymerase catalytic subunit P04293 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. Sergerie Y, Boivin G: Hydroxyurea enhances the activity of acyclovir and cidofovir against herpes simplex virus type 1 resistant strains harboring mutations in the thymidine kinase and/or the DNA polymerase genes. Antiviral Res. 2007 Sep 17;. Pubmed
    4. Suzuki M, Okuda T, Shiraki K: Synergistic antiviral activity of acyclovir and vidarabine against herpes simplex virus types 1 and 2 and varicella-zoster virus. Antiviral Res. 2006 Nov;72(2):157-61. Epub 2006 May 30. Pubmed
    5. Liu S, Knafels JD, Chang JS, Waszak GA, Baldwin ET, Deibel MR Jr, Thomsen DR, Homa FL, Wells PA, Tory MC, Poorman RA, Gao H, Qiu X, Seddon AP: Crystal structure of the herpes simplex virus 1 DNA polymerase. J Biol Chem. 2006 Jun 30;281(26):18193-200. Epub 2006 Apr 24. Pubmed

    3. DNA polymerase catalytic subunit

    Kind: protein

    Organism: HHV-3

    Pharmacological action: yes

    Actions: inhibitor

    Components

    Name UniProt ID Details
    DNA polymerase catalytic subunit P09252 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. Sergerie Y, Boivin G: Hydroxyurea enhances the activity of acyclovir and cidofovir against herpes simplex virus type 1 resistant strains harboring mutations in the thymidine kinase and/or the DNA polymerase genes. Antiviral Res. 2007 Sep 17;. Pubmed
    4. Suzuki M, Okuda T, Shiraki K: Synergistic antiviral activity of acyclovir and vidarabine against herpes simplex virus types 1 and 2 and varicella-zoster virus. Antiviral Res. 2006 Nov;72(2):157-61. Epub 2006 May 30. Pubmed
    5. Liu S, Knafels JD, Chang JS, Waszak GA, Baldwin ET, Deibel MR Jr, Thomsen DR, Homa FL, Wells PA, Tory MC, Poorman RA, Gao H, Qiu X, Seddon AP: Crystal structure of the herpes simplex virus 1 DNA polymerase. J Biol Chem. 2006 Jun 30;281(26):18193-200. Epub 2006 Apr 24. Pubmed

    1. Solute carrier family 22 member 1

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: inhibitor

    Components

    Name UniProt ID Details
    Solute carrier family 22 member 1 O15245 Details

    References:

    1. Takeda M, Khamdang S, Narikawa S, Kimura H, Kobayashi Y, Yamamoto T, Cha SH, Sekine T, Endou H: Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J Pharmacol Exp Ther. 2002 Mar;300(3):918-24. Pubmed

    2. 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. Takeda M, Khamdang S, Narikawa S, Kimura H, Kobayashi Y, Yamamoto T, Cha SH, Sekine T, Endou H: Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J Pharmacol Exp Ther. 2002 Mar;300(3):918-24. Pubmed
    2. Wada S, Tsuda M, Sekine T, Cha SH, Kimura M, Kanai Y, Endou H: Rat multispecific organic anion transporter 1 (rOAT1) transports zidovudine, acyclovir, and other antiviral nucleoside analogs. J Pharmacol Exp Ther. 2000 Sep;294(3):844-9. Pubmed

    3. Solute carrier family 22 member 8

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate inhibitor

    Components

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

    References:

    1. Takeda M, Khamdang S, Narikawa S, Kimura H, Kobayashi Y, Yamamoto T, Cha SH, Sekine T, Endou H: Human organic anion transporters and human organic cation transporters mediate renal antiviral transport. J Pharmacol Exp Ther. 2002 Mar;300(3):918-24. Pubmed
    2. Ohtsuki S, Asaba H, Takanaga H, Deguchi T, Hosoya K, Otagiri M, Terasaki T: Role of blood-brain barrier organic anion transporter 3 (OAT3) in the efflux of indoxyl sulfate, a uremic toxin: its involvement in neurotransmitter metabolite clearance from the brain. J Neurochem. 2002 Oct;83(1):57-66. Pubmed
    3. Cha SH, Sekine T, Fukushima JI, Kanai Y, Kobayashi Y, Goya T, Endou H: Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol. 2001 May;59(5):1277-86. Pubmed

    4. Ileal sodium/bile acid cotransporter

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Ileal sodium/bile acid cotransporter Q12908 Details

    References:

    1. Tolle-Sander S, Lentz KA, Maeda DY, Coop A, Polli JE: Increased acyclovir oral bioavailability via a bile acid conjugate. Mol Pharm. 2004 Jan 12;1(1):40-8. Pubmed

    5. Multidrug and toxin extrusion protein 1

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Multidrug and toxin extrusion protein 1 Q96FL8 Details

    References:

    1. Nies AT, Damme K, Schaeffeler E, Schwab M: Multidrug and toxin extrusion proteins as transporters of antimicrobial drugs. Expert Opin Drug Metab Toxicol. 2012 Dec;8(12):1565-77. doi: 10.1517/17425255.2012.722996. Epub 2012 Sep 13. Pubmed

    6. Multidrug and toxin extrusion protein 2

    Kind: protein

    Organism: Human

    Pharmacological action: unknown

    Actions: substrate

    Components

    Name UniProt ID Details
    Multidrug and toxin extrusion protein 2 Q86VL8 Details

    References:

    1. Nies AT, Damme K, Schaeffeler E, Schwab M: Multidrug and toxin extrusion proteins as transporters of antimicrobial drugs. Expert Opin Drug Metab Toxicol. 2012 Dec;8(12):1565-77. doi: 10.1517/17425255.2012.722996. Epub 2012 Sep 13. Pubmed

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