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Pathway Description
Valacyclovir Action Pathway
Homo sapiens
Drug Action Pathway
Valaciclovir (valacyclovir), also known as the brand name Valtrex, is an guanine nucleoside antiviral used to treat herpes exacerbations. Valaciclovir is the L-valine ester of aciclovir. Valacyclovir is rapidly and almost completely converted in man to aciclovir and valine, likely by the enzyme valacyclovir hydrolase. Aciclovir is transported from the liver into the blood via a drug transporter, then into the effected cells.
Acyclovir is a guanosine analog used to treat herpes simplex, varicella zoster, herpes zoster, herpes labialis, and acute herpetic keratitis. Acyclovir is becomes acyclovir monophosphate due to the action of viral thymidine kinase.5 Acyclovir monophosphate is converted to the diphosphate form by guanylate kinase.1 Acyclovir diphosphate is converted to acyclovir triphosphate by nucleoside diphosphate kinase, pyruvate kinase, creatine kinase, phosphoglycerate kinase, succinyl-CoA synthetase, phosphoenolpyruvate carboxykinase and adenylosuccinate synthetase. Acyclovir triphosphate inhibits the activity of DNA polymerase by competing with its substrate dGTP. Acyclovir triphosphate also gets incorporated into viral DNA, but since it lacks the 3'-OH group which is needed to form the 5′ to 3′ phosphodiester linkage essential for DNA chain elongation, this causes DNA chain termination, preventing the growth of viral DNA. Less Viral DNA is transported into the nucleus, therefore, less viral DNA is integrated into the host DNA. Less viral proteins produced, fewer viruses can form.
References
Valacyclovir Pathway References
Beutner KR: Valacyclovir: a review of its antiviral activity, pharmacokinetic properties, and clinical efficacy. Antiviral Res. 1995 Dec;28(4):281-90. doi: 10.1016/0166-3542(95)00066-6.
Pubmed: 8669888
Perry CM, Faulds D: Valaciclovir. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in herpesvirus infections. Drugs. 1996 Nov;52(5):754-72. doi: 10.2165/00003495-199652050-00009.
Pubmed: 9118821
De Clercq E, Li G: Approved Antiviral Drugs over the Past 50 Years. Clin Microbiol Rev. 2016 Jul;29(3):695-747. doi: 10.1128/CMR.00102-15.
Pubmed: 27281742
Groves MJ: Genital Herpes: A Review. Am Fam Physician. 2016 Jun 1;93(11):928-34.
Pubmed: 27281837
Sergerie Y, Boivin G: Thymidine kinase mutations conferring acyclovir resistance in herpes simplex type 1 recombinant viruses. Antimicrob Agents Chemother. 2006 Nov;50(11):3889-92. doi: 10.1128/AAC.00889-06. Epub 2006 Sep 18.
Pubmed: 16982796
Huang L, Ishii KK, Zuccola H, Gehring AM, Hwang CB, Hogle J, Coen DM: The enzymological basis for resistance of herpesvirus DNA polymerase mutants to acyclovir: relationship to the structure of alpha-like DNA polymerases. Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):447-52. doi: 10.1073/pnas.96.2.447.
Pubmed: 9892653
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. doi: 10.2165/00003495-198937030-00002.
Pubmed: 2653790
King DH: History, pharmacokinetics, and pharmacology of acyclovir. J Am Acad Dermatol. 1988 Jan;18(1 Pt 2):176-9. doi: 10.1016/s0190-9622(88)70022-5.
Pubmed: 2828440
Miller WH, Miller RL: Phosphorylation of acyclovir diphosphate by cellular enzymes. Biochem Pharmacol. 1982 Dec 1;31(23):3879-84. doi: 10.1016/0006-2952(82)90305-7.
Pubmed: 7159465
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