Previous studies with rats indicate that nifedipine undergoes both hepatic and extrahepatic presystemic metabolism after peroral (po) administration, and that its bioavailability is increased and absorption delayed by concomitant administration of grapefruit juice concentrate (GJC). Hence, the effects of GJC could be to delay stomach emptying and inhibit nifedipine metabolism in the small-intestinal wall and liver or, alternatively, to impede nifedipine absorption until reaching the large intestine where gut wall presystemic metabolism is not a factor. The mechanism(s) of action of GJC might be partially resolved by comparison with orange juice concentrate (OJC), which has a similar consistency but lacks inhibitory effects on nifedipine presystemic metabolism, and also by giving regular-strength solutions of the two juices, both on which should not significantly affect stomach emptying. This study compared the po bioavailability of nifedipine (6 mg kg -1 ) in male Sprague -Dawley rats coadministered GJC, OJC, grapefruit juice regular strength (GJRS), orange juice regular strength (OJRS), or (tap) water. Nifedipine plasma concentration-time profiles in the GJRS, OJRS, and (tap) water groups displayed a single peak. Both GJC and OJC groups have double-peak profiles (indicating delayed gastric emptying); however, the majority of the nifedipine dose in both cases was absorbed during the interval of the second peak, which occurred several hours postdosing. GJC significantly increased nifedipine bioavailability (relative bioavailability 2.02, compared with (tap) water), indicating that GJC may affect both extrahepatic and hepatic first-pass metabolism, although a reduction in systemic nifedipine clearance cannot be ruled out. Surprisingly, GJRS had no significant effect on nifedipine bioavailability. OJC did not increase nifedipine bioavailability, further suggesting that the delay in nifedipine absorption by GJC or OJC results from delayed gastric emptying.