The objective of this study was to determine the effects of grapefruit juice and seville orange juice on dextromethorphan (DM) pharmacokinetics. Eleven healthy volunteers were studied over a 3-week period consisting of 5 study days each separated by a three-day washout. All subjects refrained from drinking caffeine containing beverages (coffee, soda, etc.) 8 h before orally taking DM (30 mg) with 200 ml water, 200 ml grapefruit juice, 200 ml water, 200 ml seville orange juice, and 200 ml water on Study Days 1 to 5. Aliquots of urine samples were assayed and analysed for DM, and the DM metabolites dextrorphan, 3-methoxymorphinan and 3-hydroxymorphinan using a validated HPLC method employing a phenyl column and a fluorescence detection. Results suggests that DM could provide some useful information on P-glycoprotein or related membrane efflux protein activity in the human gastro-intestinal tract. Bioavailability (F) of DM increased significantly with grapefruit and seville orange juice, but only returned to half the baseline value after three days of washout. This confirms that grapefruit and seville orange juice are long-lasting and perhaps irreversible inhibitors of gut CYP3A/P-glycoprotein. Grapefruit and seville orange juice appeared to have the same overall effect on DM pharmacokinetics. In addition, this paper presents a novel method of phenotyping for CYP2D6, CYP3A and P-glycoprotein using DM as a probe.