Renal cytochrome P-450 levels, metabolism of acetaminophen (APAP) and aminopyrine, and activities of several phase II-associated enzymes [UDPGT, beta-glucuronidase, and glutathione-S-transferase (GST)] were determined in sedentary and exercised young and middle-aged Fischer-344 male rats. After an 8-week exercise regimen consisting of treadmill running at a moderate intensity, renal microsomal cytochrome P-450 levels were increased 60% and 37% in young and middle-aged runners, respectively. Exercise was found to increase renal deacetylation of APAP to the nephrotoxic metabolite p-aminophenol by 54% in young and 26% in middle-aged rats. Aminopyrine N-demethylase activity was increased 97% in the young runners only. In contrast, UDPGT, beta-glucuronidase, and GST activities were unchanged by treadmill running. NADPH-cytochrome c reductase activity, determined in young animals only, was also unaltered by exercise. Advanced age decreased renal cortical cytochrome P-450 content by 34% while having no effect on p-aminophenol production. Aminopyrine N-demethylase activity was increased by 130% with increased age. The only phase II-associated enzyme altered by age was GST activity, as sedentary middle-aged animals exhibited a 43% decrease in activity when compared with young rats. Young exercised rats did not gain weight as rapidly as sedentary rats, and middle-aged rats had a slight loss in weight during exercise. Moreover, running resulted in 30-36% less food consumption during the experimental period. In conclusion, this study demonstrated that exercise increased renal phase I drug metabolism without influencing phase II processes; furthermore, a substrate-specific modification of the response to exercise was observed in the aged rats.(ABSTRACT TRUNCATED AT 250 WORDS)