Grapefruit juice (GFJ) has been shown to affect the pharmacokinetics of a large number of drugs, essentially by inhibition of efflux transporters and CYP3A4 monooxygenase in the small intestine. The GFJ dose usually used in human studies was one glass single-strength (1x). Information on a respective dose-response relationship is not available. We investigated the effect of GFJ of different concentration (0.25 x, 0.5x, 1x, 2x) dosed in biweekly intervals in 19 volunteers. Components considered responsible for drug interactions, naringin, naringenin, bergamottin, and 6',7'-dihydroxybergamottin were determined by LC-tandem mass spectrometry. Immediately after ingestion of GFJ, participants took an aqueous solution of dextromethorphan (DEX) as probe drug. Urine was collected in two sampling periods, 0-2 and 2-4h, and excreted amounts of DEX and five metabolites associated with CYP3A4 and/or CYP2D6 enzyme activity were determined. Effects of GFJ were analyzed by the Wilcoxon matched-pairs signed-rank test against an average of four water control experiments. Two effects were highly significant: (i) a delay of total metabolite excretion in the first 2h and (ii) an inhibition of the CYP3A4-dependent metabolic pathways. Effect magnitude and significance levels were dose-dependent and indicated 200 ml 1x GFJ as "lowest observed effect level" LOEL.
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