ESTROGENS
CAUTIONS
DRUG INTERACTIONS
DRUG-FOOD COMBINATIONS
C) Grapefruit Juice
1) Interaction Effect: increased plasma concentrations of estrogens
2) Summary: Inhibitors of cytochrome P450 3A4, such as grapefruit juice, may increase plasma concentrations of estrogens and may result in side effects of estrogen (Prod Info ClimaraPro(TM), 2003). Concomitant grapefruit juice intake with ethinyl estradiol increased serum concentrations of estrone and ethinyl estradiol. However, the clinical significance of this interaction is unclear (Schubert et al, 1994; Weber et al, 1996).
3) Severity: moderate
4) Onset: rapid
5) Substantiation: probable
6) Clinical Management: Monitor for signs and symptoms of increased estrogen plasma concentrations such as hypertension, depression, headache, thromboembolism, fluid retention, abdominal cramps, bloating, and weight gain.
7) Probable Mechanism: inhibition of cytochrome P450 3A4-mediated estrogen metabolism of grapefruit juice
8) Literature Reports
a) Estrone plasma level was increased when 17,beta-estradiol was taken concomitantly with grapefruit juice. Eight subjects who had bilateral ovariectomy was included in this two-way single dose randomized crossover study. There were 2 crossover periods each lasting 8 days and separated by a 1-week washout period. The study drug was 17,beta-estradiol micronized tablets, in Trisekvens(R)-Novo Nordisk taken as a single dose of 2 mg with 200 mL of either grapefruit juice (Old South, Lykes Paso Packing Co., Florida; 100 mL frozen juice plus 100 mL water; containing 450 mcg/mL naringenin) or placebo juice (Gatorade without any flavonoids). No adverse events were reported. Plasma levels of 17,beta-estradiol was not significantly different between the two groups. However, the area under the concentration time curve from 0 to forty-eight hours (AUC,0-48) and AUC,0-192 for estrone (an active estrogen and a metabolic product of 17,beta-estradiol) was significantly increased (26.08 nmol-h/L versus 22.51 nmol-h/L, p=0.050 and 35.12 nmol-h/L versus 27.56 nmol-h/L, p=0.015, respectively), indicating a metabolic step after estrone may be inhibited. The maximal concentration (Cmax) and AUC,0-192 of combined 17,beta-estradiol plus estrone was significantly increased (1.3 nmol/L versus 1.12 nmol/L, p=0.038 and 39.58 nmol-h/L versus 31.41 nmol-h/L, p=0.036, respectively). The effect of grapefruit juice in this study was relatively small and may be of minimal clinical significance (Schubert et al, 1994).
b) Concomitant intake of grapefruit juice raised 17,alpha-ethinyl estradiol serum concentrations. Thirteen healthy females participated in this two-way randomized crossover study in Germany. There was 2 study days separated by the woman's menstrual cycle. At day 4 +/- 1 of the menstrual cycle, subjects received 100 mL of either herbal tea or grapefruit juice (with 887 mg/mL naringin) on an empty stomach. Half an hour later the women took 0.025 mg of 17,alpha-ethinylestradiol together with 100 mL of the corresponding fluids. Two hundred milliliters of the corresponding fluids were also taken every 3 hours up to 4 times on the day of testing. The mean Cmax increased by 137% (from 85 pg/mL to 117 pg/mL, p = 0.009). The AUC,0-8 was significantly higher with grapefruit juice (596 pg-h/mL versus 457 pg-h/mL, p=0.19). The clinical significance of this interaction remains to be determined (Weber et al, 1996).
3.5.4 Drug-Tobacco Combinations
A) Tobacco
1) Interaction Effect: an increased risk of cardiovascular disease
2) Summary: The use of combination contraceptives with tobacco smoking (more than 15 cigarettes daily) may increase the risk of cardiovascular adverse effects in persons older than 35 years (Frederiksen & Ravenholt, 1970; Crawford et al, 1981). The use of combination contraceptives and tobacco smoking may significantly increase the risk of myocardial infarction, subarachnoid hemorrhage, venous thromboembolism, and other strokes (Petitti et al, 1979; Shapiro et al, 1979; Stadel, 1981a; Stadel, 1981).
3) Severity: minor
4) Onset: delayed
5) Substantiation: theoretical
6) Clinical Management: Combination contraceptive users should be cautioned regarding the dangers of tobacco smoking and should be advised to discontinue smoking.
7) Probable Mechanism: unknown