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 inhibition in enterocytes. Our main objective was to determine whether grapefruit juice alters the bioavailability of digoxin, a P-glycoprotein substrate. The secondary objective was to determine whether the magnitude of the pharmacokinetic interaction was influenced by P-glycoprotein genetic polymorphism. Methods. Twelve healthy volunteers participated in this open randomized crossover study comparing the effect of grapefruit juice consumption (versus water) on the pharmacokinetics of a single oral dose of digoxin (0.5 mg). The P-glycoprotein genotype was determined according to MDRI genetic polymorphism in exon 26 (C3435T). Results. Grapefruit juice had no significant effect on the maximum plasma drug concentration (C-max) of digoxin or the area under the plasma concentration-time curve (AUC) from time zero to 48 hours. However, there was a 9% increase 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 renal clearance remained unchanged during both periods. No relationship between MDRI C3435T genotype and early digoxin pharmacokinetic changes could be detected. Conclusion: The modest changes in digoxin pharmacokinetics observed during grapefruit juice ingestion do not support an important P-glycoprotein inhibition. Under our experimental conditions, grapefruit juice-mediated P-glycoprotein inhibition does not appear to play a relevant role in drug interactions, at least when assesed by use of digoxin disposition kinetics.