GRAPEFRUIT JUICE AND ORANGE JUICE EFFECTS ON THE BIOAVAILABILITY OF NIFEDIPINE IN THE RAT

Previous studies with rats indicate that nifedipine undergoes both hep atic and extrahepatic presystemic metabolism after peroral (po) admini stration, and that its bioavailability is increased and absorption del ayed by concomitant administration of grapefruit juice concentrate (GJ C). Hence, the effects of GJC could be to delay stomach emptying and i nhibit nifedipine metabolism in the small-intestinal wall and liver or , alternatively, to impede nifedipine absorption until reaching the la rge intestine where gut wall presystemic metabolism is not a factor. T he mechanism(s) of action of GJC might be partially resolved by compar ison with orange juice concentrate (OJC), which has a similar consiste ncy 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 S prague-Dawley rats coadministered GJC, OJC, grapefruit juice regular s trength (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 hav e 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 postdos ing. 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, althou gh a reduction in systemic nifedipine clearance cannot be ruled out. S urprisingly, GJRS had no significant effect on nifedipine bioavailabil ity. OJC did not increase nifedipine bioavailability, further suggesti ng that the delay in nifedipine absorption by GJC or OJC results from delayed gastric emptying. (C) 1998 John Wiley & Sons, Ltd.