Effect of grapefruit juice on digoxin pharmacokinetics in humans

Objectives. Grapefruit juice is responsible for drug interactions mediated by intestinal cytochrome P4503A4 inhibition and possibly P-glycoprotein inh ibition in enterocytes. Our main objective was to determine whether grapefr uit juice alters the bioavailability of digoxin, a P-glycoprotein substrate . The secondary objective was to determine whether the magnitude of the pha rmacokinetic interaction was influenced by P-glycoprotein genetic polymorph ism. Methods. Twelve healthy volunteers participated in this open randomized cro ssover study comparing the effect of grapefruit juice consumption (versus w ater) on the pharmacokinetics of a single oral dose of digoxin (0.5 mg). Th e P-glycoprotein genotype was determined according to MDRI genetic polymorp hism in exon 26 (C3435T). Results. Grapefruit juice had no significant effect on the maximum plasma d rug concentration (C-max) of digoxin or the area under the plasma concentra tion-time curve (AUC) from time zero to 48 hours. However, there was a 9% i ncrease in the digoxin AUC from time zero to 4 hours and from time zero to 24 hours (P = .01) during grapefruit juice administration. The digoxin rena l clearance remained unchanged during both periods. No relationship between MDRI C3435T genotype and early digoxin pharmacokinetic changes could be de tected. Conclusion: The modest changes in digoxin pharmacokinetics observed during grapefruit juice ingestion do not support an important P-glycoprotein inhib ition. Under our experimental conditions, grapefruit juice-mediated P-glyco protein inhibition does not appear to play a relevant role in drug interact ions, at least when assesed by use of digoxin disposition kinetics.