Effect of grapefruit juice on digoxin pharmacokinetics in humans.
OBJECTIVE
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.


CONCLUSIONS
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.
Becquemont
L
L
Department of Pharmacology and Clinical Investigation Center, Saint-Antoine Hospital, Université Pierre et Marie Curie, 27 rue de Chaligny, 75012 Paris, France. laurent.becquemont@chusa.jussieu.fr
Verstuyft
C
C
Kerb
R
R
Brinkmann
U
U
Lebot
M
M
Jaillon
P
P
Funck-Brentano
C
C
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D019540:Area Under Curve; D001628:Beverages; D002957:Citrus; D018592:Cross-Over Studies; D004077:Digoxin / Q000493:pharmacokinetics*; D018565:Food-Drug Interactions; D005838:Genotype; D006801:Humans; D011110:Polymorphism, Genetic
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004077:Digoxin