Metabolic and pharmacokinetic studies following oral administration of ¹⁴C-famciclovir to healthy subjects

Abstract

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 μg 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 μg/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 μg/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 μg/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.