Prodrugs pp 1369-1376 | Cite as

Case Study: Valacyclovir: A Prodrug of Acyclovir

  • Melissa D. Antman
  • Olafur S. Gudmundsson
Part of the Biotechnology: Pharmaceutical Aspects book series (PHARMASP, volume V)


Valacyclovir is an L-valyl ester prodrug of acyclovir that is used for the treatment of herpes, varicella zoster, and cytomegaloviruses. Valacyclovir was developed to increase the oral absorption and plasma levels of acyclovir. Increased plasma concentrations of acyclovir are important in maintaining antiviral activity, especially in immunocompromised patients and in the treatment of less sensitive viruses such as VZV and CMV (Beauchamp et al., 1992). Suboptimal exposures can lead to more resistant viral strains. To achieve high enough exposures, acyclovir must be dosed intravenously or in multiple high doses (de Miranda and Burnette, 1994). In the design of valacyclovir, the following criteria were met: it was as safe as acyclovir, efficiently converted, and gave exposures after oral administration that were comparable to plasma levels of intravenously dosed acyclovir. Several reviews describe the development, pharmacokinetics, and efficacy of valacyclovir (Crooks and Murray 1994; Beutner, 1995; Perry and Faulds, 1996).


Amino Acid Ester Resistant Viral Strain Antiviral Nucleoside Intestinal Brush Border Membrane Vesicle Peptide Transporter PEPT1 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Balimane PV, Tamai I, Guo A, Nakanishi T, Kitada H, Leibach FH, Tsuji A, and Sinko PJ. Direct Evidence for Peptide Transporter (PepT1)-mediated Uptake of a Nonpeptide Prodrug, Valacyclovir. Biochem Biophys Res Commun 1998; 250:246–251PubMedCrossRefGoogle Scholar
  2. Beauchamp LM, Orr GF, de Miranda P, Burnette T, and Krenitsky TA. Amino Acid Ester Prodrugs of Acyclovir. Antivir Chem Chemother 1992; 3:157–164Google Scholar
  3. Beutner KR. Valacyclovir: A Review of its Antiviral Activity, Pharmacokinetic Properties, and Clinical Efficacy. Antiviral Res 1995; 28:281–290PubMedCrossRefGoogle Scholar
  4. Burnette TC and de Miranda P. Metabolic Disposition of the Acyclovir Prodrug Valaciclovir in the Rat. Drug Metab Disp 1994; 22:60–64Google Scholar
  5. Burnette TC, Harrington JA, Reardon JE, Merrill BM, and de Miranda P. Purification and Characterization of a Rat Liver Enzyme that Hydrolyzes Valaciclovir, the L-Valyl Ester Prodrug of Acyclovir. J Biol Chem 1995; 270:15827–15831PubMedCrossRefGoogle Scholar
  6. Crooks RJ, and Murray A. Valaciclovir—A Review of a Promising New Antiherpes Agent. Antivir Chem Chemother 1994; 5,(Suppl. 1):31–37Google Scholar
  7. de Miranda P and Blum MR. Pharmacokinetics of Acyclovir after Intravenous and Oral Administration. J Antimicrob Chemother 1983; 12(Suppl. B):29–37PubMedGoogle Scholar
  8. de Miranda P, and Burnette TC. Metabolic Fate and Pharmacokinetics of the Acyclovir Prodrug Valaciclovir in Cynomologus Monkeys. Drug Metab Disp 1994; 22:55–59Google Scholar
  9. de Miranda P, and Good SS. Species Differences in the Metabolism and Disposition of Antiviral Nucleoside Analogs: 1. Acyclovir. Antivir Chem Chemother 1992; 3:1–8Google Scholar
  10. de Vrueh RL, Smith PL, and Lee C-P. Transport of L-Valine-Acyclovir via the Oligopeptide Transporter in the Human Intestinal Cell Line, Caco-2. J Pharmacol Exp Ther 1998; 286:1166–1170PubMedGoogle Scholar
  11. Ganapathy ME, Huang W, Wang H, Ganapathy V, and Leibach FH. Valacyclovir: A Substrate for the Intestinal and Renal Peptide Transporters PEPT1 and PEPT2. Biochem Biophys Res Commun 1998; 246:470–475PubMedCrossRefGoogle Scholar
  12. Guo A, Hu P, Balimane PV, Leibach FH, and 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; 289:448–454PubMedGoogle Scholar
  13. Han H-K, de Vrueh RL, Rhie JK, Covitz K-M, Smith PL, Lee C-P, Oh D-M, Sadee W, and Amidon GL. 5′-Amino Acid Esters of Antiviral Nucleosides, Acyclovir, and AZT Are Absorbed by the Intestinal PEPT1 Peptide Transporter. Pharm Res 1998; 15:1154–1159PubMedCrossRefGoogle Scholar
  14. Kim I, Chu X-Y, Kim S, Provoda CJ, Lee K-D, and Amidon GL. Identification of a Human Valacyclovirase. Biphenyl Hydrolase-like Protein as Valacyclovir Hydrolase. J Biol Chem 2003; 278:25348–25356PubMedCrossRefGoogle Scholar
  15. Landowski CP, Sun D, Foster DR, Menon SS, Barnett JL, Welage LS, Ramachandran C, and Amidon GL. Gene Expression in the Human Intestine and Correlation with Oral Valacyclovir Pharmacokinetic Parameters. J Pharmacol Exp Ther 2003; 306:778–786PubMedCrossRefGoogle Scholar
  16. Perry CM, and Faulds D. Valaciclovir: A Review of its Antiviral Activity, Pharmacokinetic Properties and Therapeutic Efficacy in Herpesvirus Infections. Drugs 1996; 52:754–772PubMedCrossRefGoogle Scholar
  17. Sawada K, Terada T, Saito H, Hashimoto Y, and Inui K-I. Recognition of L-Amino Acid Ester Compounds by Rat Peptide Transporters PEPT1 and PEPT2. J Pharmacol Exp Ther 1999; 291:705–709PubMedGoogle Scholar
  18. Sinko PJ, and Balimane PV. Carrier-mediated Intestinal Absorption of Valacyclovir, the L-Valyl Ester Prodrug of Acyclovir: 1. Interactions with Peptides, Organic Anions and Organic Cations in Rats. Biopharm Drug Disp 1998; 19:209–217CrossRefGoogle Scholar
  19. Smiley ML, Murray A, and de Miranda P. Valacyclovir HCl (Valtrex): An Acyclovir Prodrug with Improved Pharmacokinetics and Better Efficacy for Treatment of Zoster. Adv Exp Med Biol 1996; 394:33–39PubMedGoogle Scholar
  20. Soul-Lawton J, Seaber E, On N, Wootton R, Rolan P, and Posner J. Absolute Bioavailability and Metabolic Disposition of Valaciclovir, the L-Valyl Ester of Acyclovir, Following Oral Administration to Humans. Antimicrob Agents Chemother 1995; 39:2759–2764PubMedGoogle Scholar
  21. Weller S, Blum MR, Doucette M, Burnette T, Cederberg DM, de Miranda P, and Smiley ML. Pharmacokinetics of the Acyclovir Pro-Drug Valaciclovir after Escalating Single-and Multiple-Dose Administration to Normal Volunteers. Clin Pharmacol Ther 1993; 54:595–605PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2007

Authors and Affiliations

  • Melissa D. Antman
    • 1
  • Olafur S. Gudmundsson
    • 1
  1. 1.Discovery PharmaceuticsBristol Myers Squibb Co.Princeton

Personalised recommendations