Metabolic and pharmacokinetic studies following oral administration of famciclovir to the rat and dog.
1. Drug-related material was well absorbed following oral administration of 14C-famciclovir to the male rat at doses up to 4000 mg/kg and to the male dog at doses up to 250 mg/kg, as judged by the early onset of the peak blood or plasma concentrations of radioactivity (usually < or = 1.5h) and the rapid extensive excretion of radioactivity in the urine (57-76 and 86-89% of dose in rat and dog respectively). 2. Famciclovir underwent extensive first-pass metabolism in both species. In rat, following dosing at 40 mg/kg, famciclovir was rapidly and extensively metabolized to the active antiviral compound penciclovir, which reached peak concentrations in the plasma (mean 3.5 micrograms/ml) at 0.5 h. The 6-deoxy precursor of penciclovir, BRL 42359, was the only other major metabolite detected in rat plasma. Cmax values for BRL 42359 (mean 2.2 micrograms/ml) were also achieved at 0.5 h. In dog, extensive conversion of famciclovir to penciclovir, via BRL 42359, also occurred, but its rate of formation from BRL 42359 was somewhat slower than in rat. In dog, following dosing at 25 mg/kg, Cmax values for penciclovir (mean 4.4 micrograms/ml) occurred at 3 h and were lower than the Cmax values for BRL 42359 (mean 10.0 micrograms/ml) which were achieved at 1h. 3. A dose-dependent decrease in the conversion of BRL 42359 to penciclovir occurred in both species, resulting a changes in the ratios of the plasma concentrations of the two metabolites with increasing dose. In rat, the urinary excretion of penciclovir decreased from 36% of dose at 40 mg/kg to 21% at 4000 mg/kg, and was accompanied by a corresponding increase in the urinary excretion of BRL 42359. In dog, a similar decrease in the urinary excretion of penciclovir occurred on increasing the dose of famciclovir from 25 to 250 mg/kg. 4. Penciclovir and 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 recovered in the excreta as penciclovir and BRL 42359 respectively. Corresponding recoveries of the two metabolites in the dog were 34 and 50% of dose. The metabolic fate of famciclovir in these animal species is, therefore, similar to that reported previously in man.
Filer
C W
CW
Drug Metabolism and Pharmacokinetics Department, SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, UK.
Ramji
J V
JV
Allen
G D
GD
Brown
T A
TA
Fowles
S E
SE
Hollis
F J
FJ
Mort
E E
EE
D015075:2-Aminopurine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D000212:Acyclovir / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D000077595:Famciclovir; D005243:Feces / Q000737:chemistry; D006147:Guanine; D008297:Male; D013058:Mass Spectrometry; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013056:Spectrophotometry, Ultraviolet
D000998:Antiviral Agents; D001798:Blood Proteins; C080051:BRL 42359; C053539:penciclovir; D015075:2-Aminopurine; D006147:Guanine; D000077595:Famciclovir; D000212:Acyclovir