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targets (2) transporters (3)
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Identification
Name Valaciclovir
Accession Number DB00577 (APRD00697)
Type small molecule
Groups approved
Description

Valaciclovir (INN) or valacyclovir (USAN) is an antiviral drug used in the management of herpes simplex and herpes zoster (shingles). It is a prodrug, being converted in vivo to aciclovir. It is marketed by GlaxoSmithKline under the trade name Valtrex or Zelitrex. [Wikipedia]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • valaciclovir
  • Valaciclovir Hcl
  • Valaciclovir Hydrochloride
  • Valacyclover Hydrochloric
  • Valacyclover Hydrochloride
  • Valacyclovir
  • Valacyclovir Hydrochloride
Brand names
  • Valtrex
  • Zelitrex
Brand name mixtures Not Available
Categories
  • Antiviral Agents
  • Prodrugs
CAS number 124832-27-5
Weight Average: 324.3357
Monoisotopic: 324.154603158
Chemical Formula C13H20N6O4
InChI Key InChIKey=HDOVUKNUBWVHOX-QMMMGPOBSA-N
InChI
InChI=1S/C13H20N6O4/c1-7(2)8(14)12(21)23-4-3-22-6-19-5-16-9-10(19)17-13(15)18-11(9)20/h5,7-8H,3-4,6,14H2,1-2H3,(H3,15,17,18,20)/t8-/m0/s1
Plain Text
IUPAC Name
2-[(2-amino-6-oxo-6,9-dihydro-3H-purin-9-yl)methoxy]ethyl (2S)-2-amino-3-methylbutanoate
SMILES
CC(C)[C@H](N)C(=O)OCCOCN1C=NC2=C1NC(N)=NC2=O
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Amino Acids
  • Hypoxanthines
Substructures
  • Carboxylic Acids and Derivatives
  • Acetates
  • Aliphatic and Aryl Amines
  • Ethers
  • Pyrimidines and Derivatives
  • Imidazoles
  • Heterocyclic compounds
  • Aromatic compounds
  • Purines and Purine Derivatives
  • Amino Acids
  • Cyanamides
  • Hypoxanthines
Pharmacology
Indication For the treatment or suppression of cold sores (herpes labialis), herpes zoster (shingles), genital herpes in immunocompetent individuals, and recurrent genital herpes in HIV-infected individuals.
Pharmacodynamics Valaciclovir (INN) or Valacyclovir (USAN) is a prodrug and synthetic purine nucleoside analogue with inhibitory activity against herpes simplex virus types 1 (HSV-1), 2 (HSV-2), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV). Valaciclovir is almost completely converted to acyclovir and L-valine. The inhibitory activity of valaciclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, which is then converted into acyclovir diphosphate and triphosphate by cellular enzymes. Acyclovir is selectively converted to the active triphosphate form by cells infected with herpes viruses.
Mechanism of action Valaciclovir is phosphorylated by viral thymidine kinase to acyclovir triphosphate (the active metabolite) which then inhibits herpes viral DNA replication by competitive inhibition of viral DNA polymerase, and by incorporation into and termination of the growing viral DNA chain. When used as a substrate for viral DNA polymerase, acyclovir triphosphate competitively inhibits dATP leading to the formation of 'faulty' DNA. This is where acyclovir triphosphate is incorporated into the DNA strand replacing many of the adenosine bases. This results in the prevention of DNA synthesis, as phosphodiester bridges can longer to be built, destabilizing the strand.
Absorption After oral administration, valaciclovir hydrochloride is rapidly absorbed from the gastrointestinal tract. The absolute bioavailability of acyclovir after administration of valaciclovir is 54.5% ± 9.1%.
Volume of distribution Not Available
Protein binding 13-18%
Metabolism

Valaciclovir is rapidly and almost entirely (~99%) converted to the active compound, acyclovir, and L-valine by first-pass intestinal and hepatic metabolism by enzymatic hydrolysis. Neither valaciclovir nor acyclovir is metabolized by cytochrome P450 enzymes.
Route of elimination Acyclovir accounted for 89% of the radioactivity excreted in the urine.
Half life 2.5-3.3 hours
Clearance
  • Renal cl=255 +/-  86 mL/min [healthy]
  • apparent cl=86.3 +/- 21.3 mL/min/1.73 m2 [dialysis patients]
  • apparent cl=679.16 +/- 162.76 mL/min/1.73 m2 [healthy]
Toxicity Adverse effects of overexposure might include headache and nausea.
Affected organisms
  • Human Herpes Virus
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Aurobindo pharma ltd
  • Dr reddys laboratories ltd
  • Matrix laboratories ltd
  • Mylan pharmaceuticals inc
  • Ranbaxy laboratories ltd
  • Roxane laboratories inc
  • Sandoz inc
  • Teva pharmaceuticals usa
  • Watson laboratories inc
  • Wockhardt ltd
  • Glaxosmithkline
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Valtrex 1 gm tablet 14.62 USD tablet
Valtrex 1 gm caplet 14.06 USD caplet
Valacyclovir HCl 1 gm tablet 12.87 USD tablet
Valtrex 500 mg tablet 8.36 USD tablet
Valacyclovir HCl 500 mg tablet 7.35 USD tablet
Valtrex (Caplet) 500 mg Tablet 3.82 USD tablet
Apo-Valacyclovir (Caplet) 500 mg Tablet 2.14 USD tablet
Pms-Valacyclovir (Caplet) 500 mg Tablet 2.14 USD tablet
Patents
Country Patent Number Approved Expires
United States 5879706 1996-07-19 2016-07-19
United States 4957924 1992-12-23 2009-12-23
Canada 2243237 2008-09-02 2017-01-17
Canada 1340083 1998-10-13 2015-10-13
Properties
State solid
Melting point Not Available
Experimental Properties
Property Value Source
logP -0.3 PhysProp
Predicted Properties
Property Value Source
water solubility 3.55e+00 g/l ALOGPS
logP -0.84 ALOGPS
logP -0.46 ChemAxon Molconvert
logS -1.96 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 8 ChemAxon Molconvert
hydrogen donor count 3 ChemAxon Molconvert
polar surface area 146.85 ChemAxon Molconvert
rotatable bond count 8 ChemAxon Molconvert
refractivity 80.63 ChemAxon Molconvert
polarizability 31.96 ChemAxon Molconvert
References
Synthesis Reference Not Available
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
External Links
Resource Link
KEGG Drug D00398 Link_out
KEGG Compound C07184 Link_out
PubChem Compound 60773 Link_out
PubChem Substance 46508197 Link_out
ChemSpider 54770 Link_out
BindingDB 50162073 Link_out
Therapeutic Targets Database DAP000643 Link_out
PharmGKB PA451839 Link_out
Drug Product Database 2246559 Link_out
RxList http://www.rxlist.com/cgi/generic3/valacyclovir.htm Link_out
Drugs.com http://www.drugs.com/valacyclovir.html Link_out
PDRhealth http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/val1474.shtml Link_out
Wikipedia http://en.wikipedia.org/wiki/Valaciclovir Link_out
ATC Codes
  • J05AB11
AHFS Codes Not Available
PDB Entries
FDA label Not Available
MSDS show (29.3 KB)
Interactions
Drug Interactions
Drug Interaction
Food Interactions Not Available
Targets

1. DNA polymerase

Pharmacological action: yes
Actions: inhibitor
Organism class: viral
UniProt ID: P04293 Link_out
Gene: UL30
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. Scott GM, Ng HL, Morton CJ, Parker MW, Rawlinson WD: Murine cytomegalovirus resistant to antivirals has genetic correlates with human cytomegalovirus. J Gen Virol. 2005 Aug;86(Pt 8):2141-51. Pubmed

2. Thymidine kinase

Pharmacological action: yes
Actions: inducer

In latent infection, may allow the virus to be reactivated and to grow in cells lacking a high concentration of phosphorylated nucleic acid precursors, such as nerve cells that do not replicate their genome

Organism class: viral
UniProt ID: Q9QNF7 Link_out
Gene: TK
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. Teh BS, Ayala G, Aguilar L, Mai WY, Timme TL, Vlachaki MT, Miles B, Kadmon D, Wheeler T, Caillouet J, Davis M, Carpenter LS, Lu HH, Chiu JK, Woo SY, Thompson T, Aguilar-Cordova E, Butler EB: Phase I-II trial evaluating combined intensity-modulated radiotherapy and in situ gene therapy with or without hormonal therapy in treatment of prostate cancer-interim report on PSA response and biopsy data. Int J Radiat Oncol Biol Phys. 2004 Apr 1;58(5):1520-9. Pubmed
  4. Satoh T, Teh BS, Timme TL, Mai WY, Gdor Y, Kusaka N, Fujita T, Pramudji CK, Vlachaki MT, Ayala G, Wheeler T, Amato R, Miles BJ, Kadmon D, Butler EB, Thompson TC: Enhanced systemic T-cell activation after in situ gene therapy with radiotherapy in prostate cancer patients. Int J Radiat Oncol Biol Phys. 2004 Jun 1;59(2):562-71. Pubmed
  5. Hinata N, Shirakawa T, Terao S, Goda K, Tanaka K, Yamada Y, Hara I, Kamidono S, Fujisawa M, Gotoh A: Progress report on phase I/II clinical trial of Ad-OC-TK plus VAL therapy for metastatic or locally recurrent prostate cancer: Initial experience at Kobe University. Int J Urol. 2006 Jun;13(6):834-7. Pubmed
Transporters

1. Oligopeptide transporter, small intestine isoform

Actions: substrate, inhibitor

Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides. May constitute a major route for the absorption of protein digestion end-products

UniProt ID: P46059 Link_out
Gene: SLC15A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ganapathy ME, Huang W, Wang H, Ganapathy V, Leibach FH: Valacyclovir: a substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2. Biochem Biophys Res Commun. 1998 May 19;246(2):470-5. Pubmed
  2. Han H, de Vrueh RL, Rhie JK, Covitz KM, Smith PL, Lee CP, Oh DM, Sadee W, Amidon GL: 5’-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter. Pharm Res. 1998 Aug;15(8):1154-9. Pubmed
  3. Balimane PV, Tamai I, Guo A, Nakanishi T, Kitada H, Leibach FH, Tsuji A, Sinko PJ: Direct evidence for peptide transporter (PepT1)-mediated uptake of a nonpeptide prodrug, valacyclovir. Biochem Biophys Res Commun. 1998 Sep 18;250(2):246-51. Pubmed
  4. Sawada K, Terada T, Saito H, Hashimoto Y, Inui KI: Recognition of L-amino acid ester compounds by rat peptide transporters PEPT1 and PEPT2. J Pharmacol Exp Ther. 1999 Nov;291(2):705-9. Pubmed
  5. Balimane P, Sinko P: Effect of ionization on the variable uptake of valacyclovir via the human intestinal peptide transporter (hPepT1) in CHO cells. Biopharm Drug Dispos. 2000 Jul;21(5):165-74. Pubmed
  6. Guo A, Hu P, Balimane PV, Leibach FH, Sinko PJ: Interactions of a nonpeptidic drug, valacyclovir, with the human intestinal peptide transporter (hPEPT1) expressed in a mammalian cell line. J Pharmacol Exp Ther. 1999 Apr;289(1):448-54. Pubmed

2. Oligopeptide transporter, kidney isoform

Actions: inhibitor

Proton-coupled intake of oligopeptides of 2 to 4 amino acids with a preference for dipeptides

UniProt ID: Q16348 Link_out
Gene: SLC15A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Ganapathy ME, Huang W, Wang H, Ganapathy V, Leibach FH: Valacyclovir: a substrate for the intestinal and renal peptide transporters PEPT1 and PEPT2. Biochem Biophys Res Commun. 1998 May 19;246(2):470-5. Pubmed
  2. Sawada K, Terada T, Saito H, Hashimoto Y, Inui KI: Recognition of L-amino acid ester compounds by rat peptide transporters PEPT1 and PEPT2. J Pharmacol Exp Ther. 1999 Nov;291(2):705-9. Pubmed

3. Solute carrier family 22 member 8

Actions: substrate

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)

UniProt ID: Q8TCC7 Link_out
Gene: SLC22A8 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on November 10, 2010 13:40

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.