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.

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.

Following oral administration of potassium 14C-clavulanate to four human subjects, at least 73% of the radioactive dose was absorbed. The mean absolute bioavailability was 64%. Absorption was rapid with peak plasma concentrations of radioactivity and clavulanic acid (2-6 micrograms/ml) occurring between 45 min and three hours after dosing. Values for the volume of distribution at steady-state and terminal half-life of clavulanic acid in the plasma were 12.01 and 0.8 h respectively. Following intravenous administration of clavulanic acid to the same subjects, the clearance, and volume of distribution at steady-state were 0.21 l/min, and 12.01, respectively. Clavulanic acid was the major radioactive component present in 0-24 h urine following oral dosing (23% of the dose). The two major metabolites were 2,5-dihydro-4-(2-hydroxyethyl)-5-oxo-1H-pyrrole-3-carboxylic acid (15% of the dose) and 1-amino-4-hydroxybutan-2-one (8.8% of the dose). Clavulanic acid and 1-amino-4-hydroxybutan-2-one were the major components in plasma following oral administration (52 and 21% of plasma radioactivity respectively at two hours after dosing). The major route of excretion of radioactivity following oral administration was via the urine (73% of the dose). Most of this radioactivity was excreted in the first 24 h after dosing (68% of the dose). The renal clearance of clavulanic acid was 0.1 l/min. Elimination of radioactivity also occurred via the expired air (17% of the dose) and the faeces (8% of the dose).

Radiochemically labelled (3‐14C)‐decoquinate (ethyl 6‐n‐decyloxy‐7‐ethoxy‐4‐hydroxyquinoline‐3‐carboxylate) has been synthesised and used to measure residues remaining in liver, kidney, teg muscle, breast muscle, blood, heart, fat and skin after administration to broiler chickens at a dose equivalent to 0.008% decoquinate in the feed. Residues reached their maximum levels three days after dosing began and they remained substantially constant thereafter. These levels were less than 1.0 ppm in all the tissues examined. After withdrawal of medication, residue levels fell rapidly in most tissues (<0.1 ppm after 89 h) with the exception of fat and skin.

1. A technique is described for the continuous collection of bile, for long periods, from unrestrained conscious rats housed in standard glass metabolism cages. 2. Bile is collected in cooled vessels outside the cage through a cannula which is exteriorized at the back of the neck and is protected from damage by an outer covering. 3. A minimum recovery period of three days is allowed after the operation, by which time liver function and intestinal motility are normal. 4. An extension of the technique can be used to assess enterohepatic circulation.