Valacyclovir prodrug

Balimane, P. V., et al. Direct evidence for peptide transporter (PepTl)-mediated uptake of a nonpeptide prodrug, valacyclovir. Biochem. 

Valacyclovir, the L-valyl ester of acyclovir, is a prodrug that can be administered orally in herpes zoster infections. Its absorption rate is approx, twice that of acyclovir. During passage through the intestinal wall and liver, the valine residue is cleaved by esterases, generating acyclovir. 

Acyclovir Zovirax) is a guanine nucleoside analogue most effective against HSV-1 and HSV-2, but it has some activity against VCV, CMV, and EBV. Valacyclovir (Valtrex) is the L-valine ester prodrug of acyclovir. Acyclovir is converted to its active metabolite via three phosphorylation steps. First, viral thymidine kinase converts acyclovir to acyclovir monophosphate. Next, host cell enzymes convert the monophosphate to the diphosphate and then to the active compound, acyclovir triphosphate. Because viral thymidine kinase has a much greater affinity for acyclovir triphosphate than does mammalian thymidine kinase, acyclovir triphosphate accumulates only in virus-infected cells. 

Valacyclovir (Valtrex) is the precursor or prodrug of acyclovir.89 When administered orally, valacyclovir is converted to acyclovir in the intestinal tract and liver. This conversion typically results in the eventual appearance of higher levels of acyclovir in the bloodstream, because valacyclovir is absorbed more readily from the gastrointestinal tract than acyclovir.42 Thus, administration of valacyclovir is a more effective way to achieve the therapeutic effects of acyclovir when these drugs are orally administered.42... 

Sinko, P. J., and Balimane, P. V. Carrier-mediated intestinal absorption of valacyclovir, the L-valyl ester prodrug of acyclovir I. Interactions with peptides, organic anions and organic cations in rats. Biopharm. Drug Dispos. 19(4) 209-217, 1998. 

Optimal antiviral treatment is begun within 48 to 72 hours of the first skin eruption to reduce further ocular involvement and perhaps decrease the duration of associated pain it has not been proven to prevent PHN. This optimal time course, however, should not detract from the value of antiviral therapy begim late, which may still be beneficial when initiated 3 to 7 days after eruption. Oral antivirals effectively hasten resolution of signs and symptoms, reduce viral shedding and formation of new skin lesions, and decrease both the incidence and severity of ocular complications. Controversy remains as to the best choice of oral therapy. Acyclovir 800 mg five times a day for 7 to 14 days has been the standard. Alternatively, valacyclovir, a prodrug of acyclovir, is administered at 1,000 mg three times a day and is considerably less expensive than acyclovir. Famciclovir, a prodrug of penciclovir,... 

First-pass conversion of a prodrug to an active drug has been studied in pregnancy with the drug valacyclovir (71). Orally administered valacyclovir produced three times higher plasma levels of acyclovir than when acyclovir was administered orally. How ever/ the levels achieved with valacyclovir were somewhat lower than the reported levels in normal volunteers. On the other hand/ acyclovir pharmacokinetics were/ overall/ similar to what has been reported in nonpregnant womeiT. 

Valacyclovir is an ester prodrug of acyclovir. It provides significantly better oral bioavailability compared to acyclovir. This advantage results in substantially higher serum acyclovir concentrations than is possible with oral acyclovir. In addition, fewer daily doses are required with valacyclovir (Curran and Noble, 2001). 

U87 Valaciclovir ValACV Valacyclovir. Antiviral agent. Prodrug of acyclovir. Glaxo Wellcome Inc. 

CHEMISTRY AND ANTIVIRAL ACTIVITY Acyclovir is an acyclic guanine nucleoside analog that lacks a 3 -hydroxyl on the side chain. Valacyclovir is the L-valyl ester prodrug of acyclovir. 

Figure 9.15 An example of the use of a prodrug to improve carrier-mediated transport. Valacyclovir, an L-valine ester prodrug, is transported across intestinal epithelial cell membranes by the HPTl and PEPTl transporters, and is then enzymatically hydrolyzed to the antiviral agent acyclovir before being converted to the true active component, acyclovir triphosphate, in cells.

Uptake transporter prodrug substrates have been used to improve drug absorption through GI tract. The most successful example is an antiviral prodrug valacyclovir, which shows oral bioavailability three to live times greater than its parent drug acyclovir (Weller et al., 1993). The increased oral bioavailability is attributed to PEPTl-mediated absorption, which was demonstrated by in situ rat perfusion model, Caco-2 cells, and PEPTl-transfected CHO cells (Balimane et al., 1998). 

Sinko, Biochem. Biophys. Res. Commun., 250, 246 (1998). Direct Evidence for Peptide Transporter (PepTl )-Mediated Uptake of a Nonpeptide Prodrug, Valacyclovir. 

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