Dextromethorphan (DXM) is commonly used as a probe for the metabolic activity of the debrisoquine isozyme (P-450 lID6) of the cytochrome P-450 mixed-function oxidase system. Several reports have described changes in P-450 activity with dietary alteration. This study was conducted to determine the effect of protein and calorie restriction on DXM metabolism in Sprague Dawley (SD) rats. Four-to fiveweek-old male SD rats were fed one of four dietary regimens: a regular diet containing 22.5% protein ad libitum (REGLIB); a low protein (8%) diet fed ad libitum (PROLIB); a regular protein diet, but only 50% by weight of that consumed by the REGLIB group (REG50); a low protein (8%) diet, but only 50% by weight of that consumed by the PROLIB group (PRO50). The DXM log., molar metabolic ratio (LMR) calculated as the ratio of the urinary DXM to its" metabolite dextrorphan concentration was measured at the beginning of the study and after 5 weeks of feeding. Groups REG50, PROLIB, and PRO50 received 49%, 57%, and 29% of the calorie intake and 49%, 24%, and 12% of the protein intake of group REGLIB, respectively. Their weight gain was 24%, 40%, and 3% of that gained by REGLIB. LMR significantly decreased for REGLIB and PROLIB indicating an increase in DXM metabolism. The LMR of REG50 and PRO50 did not change. DXM metabolism continues to develop in these rats during the first 7 to 8 weeks of life. Energy restriction inhibited the maturation of DXM metabolism, while protein restriction did not significantly affect DXM metabolism.