Abstract

We studied the effects of short- and long-term ingestion of grapefruit juice (GJ) on nifedipine (NFP) pharmacokinetics in rats. Thirty minutes after intraduodenal (id) administration of 2.0 ml of GJ or saline, NFP was i.v. or id administered at a dose of 3 mg/kg b.wt. No significant differences were observed in pharmacokinetic values between the two groups after i.v. administrations of NFP. By contrast, after id administration, the mean AUC value in the GJ group was approximately 1.62 times that in the control group, and the mean apparent clearance (CL) decreased by approximately 40%. In addition, 2.0 ml of GJ was orally administered twice a day (9:00 AM and 7:00 PM) for 10 consecutive days; on the 11th day the pharmacokinetics of NFP were examined again. Irrespective of route of administration (i.v. or id), NFP CL from plasma in these GJ-treated rats was considerably faster than that in the rats treated with GJ for a short (30-min) period. In microsomes prepared from the intestinal mucosa of animals receiving long-term administration of GJ, NFP oxidation activity (0.21 ± 0.02 nmol/mg/min) and P-450 content (0.045 ± 0.009 nmol/mg) were significantly lower than those in untreated rats (0.32 ± 0.05 nmol/mg/min and 0.060 ± 0.007 nmol/mg). In hepatic microsomes from the same rats, however, NFP oxidation activity (1.43 ± 0.17 nmol/mg/min) and P-450 content (0.66 ± 0.07 nmol/mg) were distinctly greater than those in untreated rats (1.00 ± 0.06 nmol/mg/min and 0.51 ± 0.04 nmol/mg). In conclusion, short-term id exposure to GJ resulted in increased NFP bioavailability, whereas long-term administration of GJ resulted in reduced bioavailability and increased CL.