Preclinical pharmacology and pharmacokinetics of the anti-hepatitis virus agent 2'-fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil in mice and rats

Abstract

The preclinical pharmacology and pharmacokinetics of 2'-fluoro-5-ethyl-1-13-D-arabinofuranosyluracil (FEAU), a selective inhibitor of herpesvirus and hepatitis virus replication, were investigated in the mouse and rat. Following intravenous (i.v.) Our earlier studies of structure-activity relationships for a series of 2'-fluoro-5-substituted 1-3-D-arabinofuranosyl pyrimidine analogs showed that 2'-fluoro-5-ethyl-1-0-D-arabinofuranosyluracil (FEAU) is a potent agent against herpes simplex virus with high selectivity in vitro (1, 3,5,8,12). FEAU has a higher affinity for HSV type 1 (HSV-1) and HSV-2 thymidine kinase than for host cell thymidine kinase (1). In vitro metabolic studies using HSV-1-infected and mock-infected Vero cells showed that 84% of FEAU is incorporated into the DNA of HSV-1-infected cells (8). FEAU is also highly effective in the treatment of simian varicella virus infection in vivo (10). In addition, recent studies have demonstrated that FEAU given either intraperitoneally or orally (p.o.) selectively inhibits the virusencoded DNA polymerase of woodchuck hepatitis virus found in the serum of chronically infected woodchucks. This inhibitory effect was immediate, nontoxic, and long lasting compared with the effects of 2'-fluoro-5-methyl-1-P-D-arabinofuranosyluracil (FMAU), 6-deoxyacyclovir(9-(2-hydroxethoxymethyl)-2-aminopurine), 9-(1,3-dihydroxy-2-* Corresponding author.

Semiautomated Radiosynthesis and Biological Evaluation of [18F]FEAU: A Novel PET Imaging Agent for HSV1-tk/sr39tk Reporter Gene Expression

“…Another 5-substituted nucleoside, FEAU, was also developed as an anti-Herpes Simplex agent [33,34] FEAU demonstrated lower cellular toxicity but is still as effective as FIAU to treat cells infected with Herpes Simplex Virus. We [8] and others [35] Mutant HSV1-tk's were initially developed to more effectively utilize acyclovir and ganciclovir (GCV) and to less effectively utilize thymidine to allow for more effective suicide gene therapy [36]. We have attempted to improve the sensitivity of imaging reporter gene expression by using an alternate substrate such as GCV, PCV, and FHBG and the mutant reporter gene HSV1-sr39tk [14].…”

Striking Species Difference in the Contribution of Concentrative Nucleoside Transporter 2 to Nucleoside Uptake between Mouse and Rat Hepatocytes

“…Therefore, the main nucleoside metabolism pathway directed by the nucleoside transport process might be different in mouse and rat hepatocytes. It has been shown that there are some differences in the clearance of nucleoside analogs in plasma in the mouse and rat (1,8). Although the relationship of these pharmacokinetic differences with our results has not been established, it would be intriguing if the different nucleoside transport pathways are related to species-dependent pharmacokinetics of nucleoside analogs.…”

Imaging of HSV-tk Reporter Gene Expression: Comparison Between [18F]FEAU, [18F]FFEAU, and Other Imaging Probes

“…There has been recent interest in two 18 F-labeled thymidine analogs, [ 18 (17)(18)(19), and hepatitis virus (20) infection. Preliminary results with radiolabeled FEAU and FFEAU have indicated that these compounds have good uptake characteristics in HSV1-tk and HSV1-sr39tk transduced cells, little or no uptake in nontransduced wild-type cells, and have lower abdominal background activity in mice and rats (11,14) compared with that obtained with For these reasons we compared FEAU and FFEAU with a series of other pyrimidine nucleoside derivatives (including FIAU) and with acycloguanosine analogs using a well-established in vitro uptake assay in the RG2TK1 cell line that has maintained stable levels of HSV1-tk expression for over 13 y.…”