Naringenin and interindividual variability in interaction of coumarin withgrapefruit juice

Grapefruit juice has been shown to enhance oral bioavailability of several drugs including coumarin. The degree of the interaction is highly variable among the individuals. Objective: The aim of the study was to evaluate the interindividual variability in the pharmacokinetic profile of three compone nts of grapefruit juice (naringin/naringenin, scopoletin, umbelliferone) an d to compare it with the pattern of coumarin-grapefruit juice interaction. Study design: A two set clinical study with the participation of 18 healthy volunteers was designed. In the first set of the experiment the total rena l recovery of naringenin, scopoletin and umbelliferone within 13 hours afte r the intake of 1 L grapefruit juice was estimated. Four individuals, who h ad demonstrated extremely high or extremely low excretion of the metabolite s in the first set, were selected for the second set. The subjects took 10 mg coumarin with 1 L grapefruit juice vs 10 mg coumarin with 1 L water in a cross-over manner. The interaction pattern was evaluated according to the time-course curves of 7-hydroxycoumarin (main metabolite of coumarin) excre ted with urine. The detailed time-course excretory profiles of naringenin a nd scopoletin from grapefruit juice were also obtained. Results: The screen ing demonstrated a significant interindividual variability in the renal exc retion of naringenin (max/min > 15), scopoletin (max/min = 6.2), umbellifer one (max/min = 3.3). The interaction between coumarin and grapefruit juice has been observed by increase in the total recovery of 7-hydroxycoumarin up to 3 mg and by delay in time of its excretion by 2-3 hours. This interacti on has been observed in 3 of 4 subjects and correlated with naringenin amou nts in the urine. The mechanism and the sites of the interaction, as well a s the causes for its wide interindividual variability are discussed in the paper.