Fate of Ingested Radiolabeled Ethynylestradiol and Its 3-Cyclopentyl Ether in Patients with Bile Fistulas

Cargill, D. Innes; Steinetz, Bernard G.; Gosnell, Elizabeth R; Beach, V. L.; Meli, A; Fujimoto, George I.; Reynolds, Benedict M.

doi:10.1210/jcem-29-8-1051

Cited by 49 publications

(11 citation statements)

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“…These data are compatible with EE2 undergoing enterohepatic circulation since it is known that EE2 is (Steinetz, Meli, Giannina & Beach, 1967;Beach, Steinetz, Giannina & Meli, 1967;Cargill, Steinetz, Gosnell, Beach, Meli, Fujimoto & Reynolds, 1969;Fotherby, 1974;Helton & Goldzieher, 1977). The end result of hepatic enzyme induction is essentially to increase the intrinsic clearance of a drug, which if it has a low extraction ratio will produce a lowering in AUC mainly due to a shortening of plasma half life; this will happen after both intravenous and oral administration.…”

Section: Discussionsupporting

confidence: 78%

Phenobarbitone Interaction With Oral Contraceptive Steroids in the Rabbit and Rat

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Breckenridge

Crawford

et al. 1980

British J Pharmacology

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1 The effect of phenobarbitone on the single dose pharmacokinetics of the synthetic steroids, ethinyloestradiol (EE2) and norethisterone, has been studied in the rabbit and rat. 2 EE2 is subject to an extensive first pass effect (96%). The plasma clearance of EE2 approaches total hepatic blood flow. It is suggested that a secondary peak in EE2 plasma concentration time curves at 5 h is due to enterohepatic recycling. Phenobarbitone had no effect on plasma EE2 concentrations following intravenous administration and produced a variable decrease after oral administration. 3 In phenobarbitone-treated rabbits, following intravenous administration of norethisterone there was no significant change in the area under the curve (AUC) compared to controls. In contrast, following oral administration of norethisterone to treated rabbits, the AUC was 20% and the peak plasma concentration 17% of that in controls.4 The data in rabbits are consistent with drugs which are highly extracted by the liver. 5 In rats, phenobarbitone had no effect on plasma norethisterone concentrations following intravenous or hepatic portal (bolus) administration, but caused a decrease in systemic availability after both infusion into the portal vein (over a period of 5 min) and oral administration. 6 It is concluded that the rate of delivery of norethisterone to the liver is important in determining whether or not enzyme induction will cause an increased first pass effect. 7 Phenobarbitone caused an increase in conjugation of norethisterone in the gastrointestinal tract of rats.

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Section: Discussionsupporting

confidence: 78%

Phenobarbitone Interaction With Oral Contraceptive Steroids in the Rabbit and Rat

Back

Breckenridge

Crawford

et al. 1980

British J Pharmacology

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“…The metabolites that are produced both by the gut wall and by the liver include sulphate and glucuronide conjugates which are then excreted in the bile. Cargill et al (1969), found, in one patient, that 27% of a single dose of ethinyloestradiol was present in the bile as conjugates, two thirds of which were sulphate conjugates and one third glucuronide conjugates. Once the bile reaches the intestine, the conjugates may be broken down to liberate unchanged ethinyloestradiol which is then reabsorbed.…”

Section: Discussionmentioning

confidence: 97%

The effects of ampicillin oral contraceptive steroids in women.

Back¹,

Breckenridge²,

MacIver³

et al. 1982

Brit J Clinical Pharma

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1 Thirteen women taking long term oral contraceptive steroids were studied while taking ampicillin (500 mg three times daily) and compared to a control cycle while not taking ampicillin.2 There were no significant changes in the plasma concentrations of ethinyloestradiol, levonorgestrel, follicle stimulating hormone or progesterone, although lower concentrations of ethinyloestradiol were noted in two women.3 We conclude that most patients taking oral contraceptive steroids do not need to take alternative contraceptive precautions while taking ampicillin.

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“…Analysis of metabolites by UV-HPLC-MS/MS con®rmed partial biotransformation of methoxychlor to mono-and bis-hydroxy metabolites, although other hydroxylated products (Blizard et al 2001), which would be indicated by the presence of (M ‡ H ‡ 16) + ions, were not evident. Mestranol was partially metabolized to a major product identi®ed as 17¬-ethinyl oestradiol, other metabolites including 2-hydroxymestrano l (Abdel Aziz and Williams 1969) and a 6-hydroxy 17¬-ethinyl oestradiol (Cargill et al 1969) have also been reported. In contrast, isoxanthohumol proved resistant to metabolism to 8-PN following incubation with Aroclor 1254-induced microsomes as revealed by UV-HPLC, and this fact was consistent with the observation that oestrogenic activity was unchanged.…”

Section: Discussionmentioning

confidence: 99%

A binary screening assay for pro-oestrogens in food: metabolic activation using hepatic microsomes and detection with oestrogen sensitive recombinant yeast cells

Coldham¹,

Horton²,

Byford³

et al. 2002

Food Additives and Contaminants

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An assay, employing microsomes prepared from rat liver and a recombinant cell bioassay (RCBA) expressing the human oestrogen receptor (alpha) linked to a reporter gene, was evaluated for the detection of pro-oestrogens in food using methoxychlor and mestranol as model compounds. Bio-activation of the hop phytoestrogen isoxanthohumol to the potent oestrogen 8-prenylnaringenin was also investigated. The oestrogenic potency values for reference standards determined with the RCBA (17beta-oestradiol = 100%) were: methoxychlor 0.0025%, mestranol 1.3%, isoxanthohumol 0.001%, and for their potential respective metabolites were: bishydroxymethoxychlor 0.015%, 17alpha-ethynyl oestradiol 69% and 8-prenylnaringenin 0.4%. Incubation of methoxychlor and mestranol (10 microM) with microsomes prepared from the liver of rats treated with Aroclor 1254 significantly increased (p < 0.001) their oestrogenic potency from 0.0021 and 2.4% to 0.015 and 8.3%, respectively. In contrast, the potency of the hop phytoestrogen isoxanthohumol was unchanged. Metabolites were identified by UV-HPLC-MS/MS as monohydroxy methoxychlor and HPTE from methoxychlor, and the major metabolite of mestranol was 17alpha-ethynyl oestradiol. There was no evidence for the metabolism of isoxanthohumol. Mestranol was also activated by microsomes induced with saline (control), beta-napthoflavone, 3-methylcholantherene, isoniazid or pregnenolone-16alpha-carbonitrile, but not phenobarbitone. These studies demonstrate the principle for use of a binary assay system for the detection of pro-oestrogens and indicate the potential value for risk assessment of endocrine disrupting chemicals.

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Fate of Ingested Radiolabeled Ethynylestradiol and Its 3-Cyclopentyl Ether in Patients with Bile Fistulas

Cited by 49 publications

References 0 publications

Phenobarbitone Interaction With Oral Contraceptive Steroids in the Rabbit and Rat

Phenobarbitone Interaction With Oral Contraceptive Steroids in the Rabbit and Rat

The effects of ampicillin oral contraceptive steroids in women.

A binary screening assay for pro-oestrogens in food: metabolic activation using hepatic microsomes and detection with oestrogen sensitive recombinant yeast cells

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