The influence of aging on the metabolism of antipyrine (AP) and hexobarbital enantiomers (R-HB and S-HB) with and without phenobarbital (PB) induction was investigated in a longitudinal study in rats aged 6, 12, 24 and 30 months. The metabolic clearances of AP (Cl(m AP)), R-HB (Cl(m R-HB)) and S-HB (Cl(m S-HB)) were used as indicators for P450 enzyme activities in vivo. This also included the assessment of the clearances of formation of three AP metabolites, 3-hydroxymethylantipyrine (Cl(→HMA)), 4-hydroxyantipyrine (Cl(→OHA)) and norantipyrine (Cl(→NORA)). Aging appeared to have little influence on the pharmacokinetics of the model compounds. By contrast, the influence of PB pretreatment on Cl(m AP) changed dramatically with aging. The extent of induction decreased from 4.5-fold at 6 months to 1.7-fold at 30 months. Aging influenced the clearances of formation of the three metabolites differentially. Cl(m S-HB) was about six times higher than Cl(m R-HB) without induction. After PB induction, S-HB did not reach detectable levels in plasma at 6, 12 and 24 months. At 30 months, PB pretreatment resulted in a significantly decreased Cl(m S-HB) when compared with the uninduced state. The extent of induction of R-HB metabolism had decreased strongly at 24 and 30 months. The present results clearly indicate that in the aged rat, the P450 enzyme system is much less sensitive to PB induction. Chemicals/CAS: 3 hydroxymethylphenazone, 18125-49-0; 4 hydroxyphenazone, 1672-63-5; cytochrome P450, 9035-51-2; hexobarbital, 1335-39-3, 50-09-9, 56-29-1, 73543-95-0; norphenazone, 89-25-8; phenazone, 60-80-0; phenobarbital, 50-06-6, 57-30-7, 8028-68-0; Antipyrine, 60-80-0; Cytochrome P-450 Enzyme System, 9035-51-2; Hexobarbital, 56-29-1; Phenobarbital, 50-06-6