Biodisposition of phenobarbital was examined in male Fischer-344 rats of different ages (3-4, 11-12, 23-24, and 32-34 months). Phenobarbital was administered intraperitoneally as a bolus (20 mg/kg) or continuously for 5 days from an implanted osmotic minipump (4.73 mg/day). Phenobarbital concentrations were determined by gas chromatography with a nitrogen-selective detector after extraction from plasma, plasma ultrafiltrate, and brain (cortex and cerebellum). Higher plasma and brain concentrations were found in the aged animals after a bolus injection or during continuous administration, and were related to decreases in the apparent plasma clearance of the drug. Apparent clearance was greater during continuous administration than following a bolus in 3- to 4-month- and in 32- to 34-month-old rats, which suggested autoinduction of phenobarbital metabolism. In addition, the plasma/brain distribution ratio of phenobarbital was elevated in the older animals.