Metabolic and pharmacokinetic studies following oral administration of 14C-famciclovir to healthy subjects.
1. Following oral administration of 14C-famciclovir (500 mg) to three healthy male subjects, drug-related material was rapidly absorbed as judged by peak plasma concentrations of radioactive material being achieved by 0.75 h (6.7 +/- 0.9 microgram equiv./ml (mean +/- SD). 2. Famciclovir underwent extensive first-pass metabolism and was only detected in the plasma of one subject at low concentrations (0.5 microgram/ml). Famciclovir was rapidly and extensively metabolized to the active antiviral compound penciclovir, which reached peak concentrations in the plasma of 3.6 +/- 0.7 microgram/ml (0.75 h). The plasma elimination half-life value for penciclovir was 2.1 +/- 0.1 h. The 6-deoxy precursor of penciclovir, BRL 42359, was the only other relatively major metabolite detected in plasma. Peak plasma concentrations of BRL 42359 (1.0 +/- 0.1 microgram/ml) were achieved at 0.5 h. 3. After 3 days, 73.0 +/- 6.1% of the radioactive dose was excreted in urine, showing that good absorption of drug-related material occurred. Renal excretion was rapid since 60.2 +/- 4.2 and 72.3 +/- 5.7% of the dose was recovered in the urine samples collected up to 6 and 24 h, respectively. A good recovery of the administered radioactive dose was obtained since a further 26.6 +/- 5.1% of the dose was excreted in the faeces over a 72-h period. 4. Penciclovir and BRL 42359 were the major metabolites detected in urine and faeces. Penciclovir accounted for 59.2 +/- 4.9 and 4.2 +/- 1.4% of the dose in 0-24 h urine and 0-48 h faeces, respectively. Corresponding values for BRL 42359 were 5.0 +/- 0.5 and 17.0 +/- 6.2%, respectively. These metabolites were identified in the biological samples using hplc-ms and ms-ms with thermospray ionization.
Filer
C W
CW
Drug Metabolism and Pharmacokinetics Department, SmithKline Beecham Pharmaceuticals, Welwyn, Herts, UK.
Allen
G D
GD
Brown
T A
TA
Fowles
S E
SE
Hollis
F J
FJ
Mort
E E
EE
Prince
W T
WT
Ramji
J V
JV
D015075:2-Aminopurine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D000284:Administration, Oral; D000328:Adult; D000998:Antiviral Agents / Q000378:metabolism*; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002250:Carbon Radioisotopes; D000077595:Famciclovir; D005243:Feces; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics; D011485:Protein Binding; D012016:Reference Values
D000998:Antiviral Agents; D001798:Blood Proteins; D002250:Carbon Radioisotopes; D011355:Prodrugs; D015075:2-Aminopurine; D000077595:Famciclovir