Case Study: Famciclovir: A Prodrug of Penciclovir
Famciclovir was designed as an orally bioavailable prodrug of penciclovir, an antiviral agent with activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella-zoster virus (VZV) (Boyd et al., 1987; 1988). Penciclovir similarly to other guanosine analogs (De Miranda and Good, 1992; De Miranda et al., 1981), is poorly absorbed when given orally to rodents and humans (Boyd et al., 1988; Filer et al., 1994). Initially, various mono and dicarboxylic esters of penciclovir were made (Harnden et al., 1987), but none of these compounds resulted in significantly improved plasma concentration, of penciclovir when administered orally (Harnden et al., 1989). The physicochemical properties of penciclovir are, furthermore, influenced by the polar guanine ring, and it was thought that modifications on that ring might lead to improved absorption. The 6-deoxy derivative was made, since it was known from previous work with acyclovir (Krenitsky et al., 1984) that it would be oxidized to form penciclovir. When esters of the 6-deoxy derivative were tested a significant increase in bioavailability was observed (Harnden et al., 1989). After further evaluation of the stability of the 6-deoxy esters (Harnden et al., 1989), the diacetyl derivative, famciclovir, was selected for further development due to its improved stability in human duodenal contents (Jarvest, 1994). For more details on the design of famciclovir the reader is referred to several recent reviews (Jarvest, 1994; Jarvest et al., 1998).
KeywordsXanthine Oxidase Antimicrob Agent Aldehyde Oxidase Acetate Ester Purine Ring
Unable to display preview. Download preview PDF.
- 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
- De Miranda P, Krasny HC, Page DA, and Elion GB. The Disposition of Acyclovir in Different Species. J Pharm Exp Ther 1981; 219:309–315Google Scholar
- Hodge RAV, and Cheng YC. The Mode of Action of Penciclovir. Antivir Chem Chemother 1993; 4:13–24Google Scholar
- Hodge RAV, Sutton D. Boyd MR, Harnden MR, and Jarvest RL. Selection of an Oral Prodrug (BRL 42810; Famciclovir) for the Antiherpes Virus Agent BRL 39123 [9-(4-Hydroxy-3-hydroxymethylbut-1-yl)guanine; penciclovir]. Antimicrob Agents Chemother 1989; 33:1765–1773Google Scholar
- Jarvest RL. Discovery and Characterization of Famciclovir (Famvir), a Novel Anti-Herpesvirus Agent. Drugs Today 1994; 30:575–588Google Scholar
- Pue MA, and Benet LZ. Pharmacokinetics of Famciclovir in Man. Antivir Chem Chemother 1993; 4(Suppl. 1):47–55Google Scholar
- Vere Hodge RA, Darlison SJ, Earnshaw DL, and Readshaw SA. Use of Isotopically Chiral [4′-13C]Famciclovir and 13C NMR to Identify the Chiral Monoacetylated Intermediates in the Conversion of Famciclovir to Penciclovir by Human Intestinal Wall Extract. Chirality 1993; 5:577–582PubMedCrossRefGoogle Scholar