In an open, randomized, cross-over study the concentrations of 17B-estradiol and estrone in serum were measured over 192 hours in 8 ovariectomized women after a single oral dose intake of 2 mg micronized 17B-estradiol. The subjects were studied with and without grapefruit juice intake containing the three natural flavonoids, naringenin, quercetin and kaempherol, which are found as glycosides in citrus fruit. These flavonoids interact with the metabolism of drugs such as 17B-estradiol and other steroids that are extensively metabolized through the P-45ONF (P450 IIIA4) enzyme or closely related P-450 systems. After administration of grapefruit juice, peak estrone (between 2-6 hours after tablet intake) concentrations increased significantly. The AUC_0-18 and AUC_0-192 for estrone but not 17B-estradiol, resulting from a single administration of micronized 17B-estradiol, were significantly altered.

Combined measured estrogens (i.e. 17B-estradiol and estrone) also increased significantly. The relationship between the AUCs for 17B-estradiol and estrone was not altered by juice intake indicating that a metabolic step after estrone, i.e. further A and/or D ring conversion was inhibited. This study demonstrates that grapefruit juice may alter the metabolic degradation of estrogens, and increase the bioavailable amounts of 17B-estradiol and its metabolite estrone, presumably by affecting the oxidative degradation of estrogens. This food interaction may be one factor behind the interindividual variability in 17B-estradiol, estrone and estriol serum concentrations after exogenous administration of 17B-estradiol to patients.

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