[6,7-3H]Ethinyloestradiol (50 microng) was administered intravenously to volunteers and the free extractable ethinyloestradiol in the plasma was measured. The compound showed a biphasic plasma decline. The half-life of the second phase was 7.5+/-1.7 (SD) hours. Administration of rifampicin (600 mg for 6 days) shifted the half-life of ethinyloestradiol to 3.3+/-0.9 h while the apparent volume of distribution for the second phase of elimination was not changed. When [2,4,6,7-3H]ethinyloestradiol (100 microng) was administered orally, some of the tritium was released by oxidative metabolism from the steroid and transformed to tritiated water (HTO) which equilibrated with whole body water. This portion, normally 7.17+/-1.66% of the tritium dose, was increased by previous administration of rifampicin to 10.62+/-2.27%. The initial rate of oxication of [2,4,6,7-3H]ethinyloestradiol was increased more than twofold by rifampicin treatment. The results are consistent with previous findings that rifampicin induces the oestrogen-2-hydroxylase in the endoplasmic reticulum of human liver, and explain the reduced effectiveness of ethinyloestradiol in oral contraceptives, if the patients are treated with rifampicin.
PIP: The interaction of rifampicin treatment with pharmacokinetics and metabolism of ethinyl estradiol (EE) was investigated in man. 50 mcg of tritiated EE was administered iv to volunteers and the free extractable EE in the plasma was measured. The compound showed a biphasic plasma decline and the 1/2-life of the 2nd phase was 7.5 hours. Administration of rifampicin (600 mg for 6 days) shifted the 1/2-life of EE to 3.3 hours while the apparent volume of distribution for the 2nd phase of elimination was not changed. When 100 mg of tritiated EE was administered orally, some of the tritium was released by oxidative metabolism from the steroid and transformed to tritiated water (HTO) which equilibrated with whole body water. The initial rate of oxidation of tritiated EE was increased more than 2-fold by rifampicin treatment. These data are consistent with previous findings that rifampicin induces the estrogen-2-hydroxylase in the endoplasmic reticulum of human liver and explains the reduced effectiveness of EE in oral contraceptives if the patients are treated with rifampicin.