Grapefruit juice-nifedipine interaction: possible involvement of several mechanisms

To develop a model based on mean residence time for better understanding the effect of grapefruit juice on the metabolism of nifedipine (NIF).

Sixteen healthy volunteers from an urban population were included. For each trial, the subjects drank water, fresh grapefruit juice or bottled grapefruit juice. Thirty minutes later, the subjects took a 10 mg capsule of NIF, orally. Plasma concentration of NIF was measured and the kinetic parameters were calculated with a non-compartmental model.

Grapefruit juice increased the bioavailability of NIF, but did not significantly reduce the drug's metabolism as shown by the approximately constant metabolite to parent drug AUC ratio (P = 0.948). There was no significant increase in the amount of non-metabolized drug absorbed during first-pass: 0.12 and 0.16 (P = 0.470) without and with grapefruit juices respectively. There was an increase in the relative bioavailability (P = 0.039) and the apparent volume of distribution (Vdm) (P = 0.025) of dehydronifedipine with grapefruit co-administration. A second peak was also observed in the NIF plasma-concentration profile when the drug is co-administered with grapefruit juice. Therefore, the most likely explanation for the double peak phenomenon is a delay in gastric emptying (+32 min with grapefruit juice) caused by the pH of grapefruit juice.

This study shows that grapefruit juice interferes with the metabolism of NIF by inhibiting NIF metabolism and slowing down the rate of gastric emptying. This study also confirms that the metabolic inhibition is not a first pass effect, but is a secondary oxidative step.