Effects of grapefruit juice on intestinal P-glycoprotein

Evaluation using digoxin in humans

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Study Objectives. To determine the effects of grapefruit juice on the pharmacokinetics of oral digoxin, a P-glycoprotein substrate not metabolized by cytochrome P450 3A4, in healthy volunteers, and to assess whether polymorphic multidrug-resistance-1 (MDR1) expression contributes to interindividual variability in digoxin disposition. Design. Prospective, open-label, unblinded, crossover study. Setting. University research center. Subjects. Seven healthy adult volunteers (four men, three women). Intervention. Each subject received a single oral dose of digoxin 1.0 mg with water or grapefruit juice with at least a 2-week washout between treatments. During the grapefruit juice phase, juice was administered 3 times/day for 5 days before digoxin administration to maximize any effect on P-glycoprotein. Measurements and Main Results. Digoxin pharmacokinetics in the presence and absence of grapefruit juice were compared. The MDR1 exon 26 C3435T genotype was determined by real-time polymerase chain reaction. Compared with water, grapefruit juice significantly reduced the digoxin absorption rate constant (3.0 ± 2.4 to 1.2 ± 1.0 hr-1, p<0.05) and increased absorption lag time (0.32 ± 0.12 to 0.53 ± 0.34 hr, p<0.05). Grapefruit juice did not affect digoxin maximum concentration (Cmax), area under the curve (AUC), elimination half-life, or renal clearance. The effect of grapefruit juice on digoxin Cmax (-45% to +41%) and AUC0-4 (-29% to +25%) varied substantially among subjects and was inversely correlated with the values during the water phase. Trends toward higher digoxin Cmax, AUC, and absorption rate constant during the water phase were found in CC homozygotes compared with subjects carrying a T allele. Conclusion. Inhibition of intestinal P-glycoprotein does not appear to play an important role in drug interactions involving grapefruit juice. Interindividual variability in response to grapefruit juice may be related to the balance of intestinal drug uptake and efflux transport.

Original languageEnglish (US)
Pages (from-to)979-987
Number of pages9
JournalPharmacotherapy
Volume23
Issue number8
DOIs
StatePublished - Aug 1 2003

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Citrus paradisi
Digoxin
P-Glycoprotein
Water
Multiple Drug Resistance
Area Under Curve
Healthy Volunteers
Pharmacokinetics
Cytochrome P-450 CYP3A
Homozygote
Drug Interactions
Cross-Over Studies
Half-Life
Real-Time Polymerase Chain Reaction
Exons
Alleles
Genotype
Kidney

All Science Journal Classification (ASJC) codes

  • Pharmacology (medical)

Cite this

Effects of grapefruit juice on intestinal P-glycoprotein : Evaluation using digoxin in humans. / Parker, Robert; Yates, Charles; Soberman, Judith E.; Laizure, Steven.

In: Pharmacotherapy, Vol. 23, No. 8, 01.08.2003, p. 979-987.

Research output: Contribution to journalArticle

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abstract = "Study Objectives. To determine the effects of grapefruit juice on the pharmacokinetics of oral digoxin, a P-glycoprotein substrate not metabolized by cytochrome P450 3A4, in healthy volunteers, and to assess whether polymorphic multidrug-resistance-1 (MDR1) expression contributes to interindividual variability in digoxin disposition. Design. Prospective, open-label, unblinded, crossover study. Setting. University research center. Subjects. Seven healthy adult volunteers (four men, three women). Intervention. Each subject received a single oral dose of digoxin 1.0 mg with water or grapefruit juice with at least a 2-week washout between treatments. During the grapefruit juice phase, juice was administered 3 times/day for 5 days before digoxin administration to maximize any effect on P-glycoprotein. Measurements and Main Results. Digoxin pharmacokinetics in the presence and absence of grapefruit juice were compared. The MDR1 exon 26 C3435T genotype was determined by real-time polymerase chain reaction. Compared with water, grapefruit juice significantly reduced the digoxin absorption rate constant (3.0 ± 2.4 to 1.2 ± 1.0 hr-1, p<0.05) and increased absorption lag time (0.32 ± 0.12 to 0.53 ± 0.34 hr, p<0.05). Grapefruit juice did not affect digoxin maximum concentration (Cmax), area under the curve (AUC), elimination half-life, or renal clearance. The effect of grapefruit juice on digoxin Cmax (-45{\%} to +41{\%}) and AUC0-4 (-29{\%} to +25{\%}) varied substantially among subjects and was inversely correlated with the values during the water phase. Trends toward higher digoxin Cmax, AUC, and absorption rate constant during the water phase were found in CC homozygotes compared with subjects carrying a T allele. Conclusion. Inhibition of intestinal P-glycoprotein does not appear to play an important role in drug interactions involving grapefruit juice. Interindividual variability in response to grapefruit juice may be related to the balance of intestinal drug uptake and efflux transport.",
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N2 - Study Objectives. To determine the effects of grapefruit juice on the pharmacokinetics of oral digoxin, a P-glycoprotein substrate not metabolized by cytochrome P450 3A4, in healthy volunteers, and to assess whether polymorphic multidrug-resistance-1 (MDR1) expression contributes to interindividual variability in digoxin disposition. Design. Prospective, open-label, unblinded, crossover study. Setting. University research center. Subjects. Seven healthy adult volunteers (four men, three women). Intervention. Each subject received a single oral dose of digoxin 1.0 mg with water or grapefruit juice with at least a 2-week washout between treatments. During the grapefruit juice phase, juice was administered 3 times/day for 5 days before digoxin administration to maximize any effect on P-glycoprotein. Measurements and Main Results. Digoxin pharmacokinetics in the presence and absence of grapefruit juice were compared. The MDR1 exon 26 C3435T genotype was determined by real-time polymerase chain reaction. Compared with water, grapefruit juice significantly reduced the digoxin absorption rate constant (3.0 ± 2.4 to 1.2 ± 1.0 hr-1, p<0.05) and increased absorption lag time (0.32 ± 0.12 to 0.53 ± 0.34 hr, p<0.05). Grapefruit juice did not affect digoxin maximum concentration (Cmax), area under the curve (AUC), elimination half-life, or renal clearance. The effect of grapefruit juice on digoxin Cmax (-45% to +41%) and AUC0-4 (-29% to +25%) varied substantially among subjects and was inversely correlated with the values during the water phase. Trends toward higher digoxin Cmax, AUC, and absorption rate constant during the water phase were found in CC homozygotes compared with subjects carrying a T allele. Conclusion. Inhibition of intestinal P-glycoprotein does not appear to play an important role in drug interactions involving grapefruit juice. Interindividual variability in response to grapefruit juice may be related to the balance of intestinal drug uptake and efflux transport.

AB - Study Objectives. To determine the effects of grapefruit juice on the pharmacokinetics of oral digoxin, a P-glycoprotein substrate not metabolized by cytochrome P450 3A4, in healthy volunteers, and to assess whether polymorphic multidrug-resistance-1 (MDR1) expression contributes to interindividual variability in digoxin disposition. Design. Prospective, open-label, unblinded, crossover study. Setting. University research center. Subjects. Seven healthy adult volunteers (four men, three women). Intervention. Each subject received a single oral dose of digoxin 1.0 mg with water or grapefruit juice with at least a 2-week washout between treatments. During the grapefruit juice phase, juice was administered 3 times/day for 5 days before digoxin administration to maximize any effect on P-glycoprotein. Measurements and Main Results. Digoxin pharmacokinetics in the presence and absence of grapefruit juice were compared. The MDR1 exon 26 C3435T genotype was determined by real-time polymerase chain reaction. Compared with water, grapefruit juice significantly reduced the digoxin absorption rate constant (3.0 ± 2.4 to 1.2 ± 1.0 hr-1, p<0.05) and increased absorption lag time (0.32 ± 0.12 to 0.53 ± 0.34 hr, p<0.05). Grapefruit juice did not affect digoxin maximum concentration (Cmax), area under the curve (AUC), elimination half-life, or renal clearance. The effect of grapefruit juice on digoxin Cmax (-45% to +41%) and AUC0-4 (-29% to +25%) varied substantially among subjects and was inversely correlated with the values during the water phase. Trends toward higher digoxin Cmax, AUC, and absorption rate constant during the water phase were found in CC homozygotes compared with subjects carrying a T allele. Conclusion. Inhibition of intestinal P-glycoprotein does not appear to play an important role in drug interactions involving grapefruit juice. Interindividual variability in response to grapefruit juice may be related to the balance of intestinal drug uptake and efflux transport.

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