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 MDR1 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 MDR1 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 assessed by use of digoxin disposition kinetics. Clinical Pharmacology & Therapeutics (2001) 70 , 311–316; doi: 10.1016/S0009‐9236(01)17221‐8