METABOLIC AND PHARMACOKINETIC STUDIES FOLLOWING ORAL-ADMINISTRATION OF FAMCICLOVIR TO THE RAT AND DOG

1. Drug-related material was well absorbed following oral administrati on of C-14-famciclovir to the male rat at doses up to 4000mg/kg and to the male dog at doses up to 250mg/kg, as judged by the early onset of the peak blood or plasma concentrations of radioactivity (usually les s than or equal to 1.5 h) and the rapid and extensive excretion of rad ioactivity in the urine (57-76 and 86-89% of dose in rat and dog respe ctively). 2. Famciclovir underwent extensive first-pass metabolism in both species. In rat, following dosing at 40 mg/kg, famciclovir was ra pidly and extensively metabolized to the active antiviral compound pen ciclovir, which reached peak concentrations in the plasma (mean 3.5 mu g/ml) at 0.5 h. The 6-deoxy precursor of penciclovir, BRL 42359, was the only other major metabolite detected in rat plasma. C-max values f or BRL 42359 (mean 2.2 mu g/ml) were also achieved at 0.5 h. In dog, e xtensive conversion of famciclovir to penciclovir, via BRL 42359, also occurred, but its rate of formation from BRL 42359 was somewhat slowe r than in rat. In dog, following dosing at 25mg/kg, C-max values for p enciclovir (mean 4.4 mu g/ml) occurred at 3 h and were lower than the C-max Values for BRL 42359 (mean 10.0 mu g/ml) which were achieved at 1 h. 3. A dose-dependent decrease in the conversion of BRL 42359 to pe nciclovir occurred in both species, resulting in changes in the ratios of the plasma concentrations of the two metabolites with increasing d ose. In rat, the urinary excretion of penciclovir decreased from 36% o f dose at 40 mg/kg to 21% at 4000 mg/kg, and was accompanied by a corr esponding increase in the urinary excretion of BRL 42359. In dog, a si milar decrease in the urinary excretion of penciclovir occurred on inc reasing the dose of famciclovir from 25 to 250 mg/kg. 4. Penciclovir a nd BRL 42359 were the major metabolites detected in urine and faeces. In rat, following dosing at 40 mg/kg, 54 and 22% of dose were recovere d in the excreta as penciclovir and BRL 42359 respectively. Correspond ing recoveries of the two metabolites in the dog were 34 and 50% of do se. The metabolic fate of famciclovir in these animal species is, ther efore, similar to that reported previously in man.