Demethylation of Mestranol to Ethinyloestradiol in Vitro and in Vivo

Kappus, H.; Bolt, Hermann M.; Remmer, H.

doi:10.1530/acta.0.0710374

Cited by 24 publications

(4 citation statements)

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“…After administration of [4-HC]mestranol 2.5% of the dose was found as labelled carbon dioxide in the expired air. About 35 % of mestranol appears to be demethylated to ethynyloestradiol in rats (Kappus et al 1972) compared to 60% in mice.…”

Section: G Metabolism Of Oestrogens In Ratsmentioning

confidence: 99%

Metabolism of Synthetic Steroids by Animals and Man

Fotherby

1974

Acta Endocrinologica

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The metabolism of naturally occurring oestrogens in humans is outlined and compared with that in other species and with the metabolism of synthetic oestrogens. There is a close similarity in humans between the metabolism of the naturally occurring oestrogens and that of ethynyl \x=req-\ oestradiol with the exception that the latter is less extensively metabolised than the former. With the exception of the baboon, the metabolism of oestrone and oestradiol appears to differ significantly in other species from that of the human. Our knowledge of the metabolism of oestrone and oestradiol and the synthetic oestrogens in the baboon is still meagre and much more information is required before one can ascertain to what extent metabolism in this species can serve as a model for that in humans.Little information is available concerning the metabolism of synthetic progestogens in species other than man and rabbits. There are many similarities between these two species both in the metabolism of progesterone and of synthetic progestogens related both to 19-nortestosterone and to 17\g=a\-hydroxyprogesterone. Insufficient information is available to know how far these similarities extend.Little is known about the in vitro metabolism of either the synthetic oestrogens or synthetic progestogens. Such information as is available does not suggest that in vitro metabolic studies, with their well-known limitations, are likely to be helpful. In vivo metabolism of oestrogensThe metabolism in humans of the naturally occurring oestrogens is briefly outlined to aid comparison with that in other species and also with the meta¬ bolism of synthetic oestrogens.A. Metabolism of oestrone and oestradiol in humans The major pathways for the metabolism of oestrogens are outlined in Fig. 1.Oestrone and oestradiol are interconvertible by 17/3-hydroxysteroid oxidoreductase, the dehydrogenation of oestradiol to oestrone being more rapid than the reduction of oestrone to oestradiol so that the equilibrium between oestrone and oestradiol favours oestrone. Although a 17a-hydroxysteroid oxidoreductase is present in man (Breuer 8c Schott 1966), 17a-oestradiol is not an important metabolite but it is important in some species. One of the main metabolic pathways for oestrone is 16a-hydroxylation leading to 16a-hydroxyoestrone and oestriol. Some of the oestriol produced is oxidized to 16-oxo-oestradiol which can undergo reduction to 16/?-hydroxyoestradiol (16-e/«oestriol). The second major pathway appears to be hydroxylation at C-2 with the formation of 2-hydroxyoestrone which is readily converted to 2-methoxyoestrone by an 0-methyl transferase. Demethylation of 2-methoxyoestrogens occurs to only a slight extent. It seems likely that oestrone sulphate rather than oestrone is the precursor for the hydroxylated metabolites found in urine (Fishman 8c Hellman 1973). Hydroxylation may also occur at C-6. Oestradiol -17 a Ha^/V^" HC 2-Hydroxyoestrone 16a-Hydroxyoestrone lóB-Hydroxyoestrone * OH O Me O HO OH -OH 2-Methoxyoestrone Oestriol Fig. 1.Metabolism of oestrog...

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Section: G Metabolism Of Oestrogens In Ratsmentioning

confidence: 99%

Metabolism of Synthetic Steroids by Animals and Man

Fotherby

1974

Acta Endocrinologica

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“…The present report extends these observations and indicates a stimulatory effect of phénobar bital on the liver microsomal metabolism of mestranol to formaldehyde and to unidentified polar metabolites. Additional studies by Kappus et al (1972) indicated a stimulatory effect of phénobarbital on the déméthylation of mestranol to ethynylestradiol.…”

Section: Discussionmentioning

confidence: 97%

Stimulatory Effect of Phenobarbital on the Metabolism of the Oral Contraceptive 17α-E thynylestradiol-3-Methyl Ether (Mestranol) by Rat Liver Microsomes

Levin¹,

Kuntzman²,

Conney³

1979

Pharmacology

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Pretreatment of rats with phenobarbital for 4 days stimulates the activity of liver microsomal enzymes that metabolize 17α-ethynylestradiol-3-methyl ether (mestranol). This effect provides an explanation for the decreased uterotropic action of mestranol in rats pretreated with phenobarbital and may provide an explanation for unwanted pregnancies in women taking oral contraceptives in combination with phenobarbital or other enzyme-inducing drugs.

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“…The uterotrophic response to norethynodrel and norethisterone was also inhibited. In an in vitro study Kappus, Bolt & Remmer (1972) observed a three fold increase in the rate of demethylation of mestranol to EE2 in phenobarbitone pretreated rats.…”

Section: Introductionmentioning

confidence: 96%

Phenobarbitone Interaction With Oral Contraceptive Steroids in the Rabbit and Rat

Back

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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Demethylation of Mestranol to Ethinyloestradiol in Vitro and in Vivo

Cited by 24 publications

References 9 publications

Metabolism of Synthetic Steroids by Animals and Man

Metabolism of Synthetic Steroids by Animals and Man

Stimulatory Effect of Phenobarbital on the Metabolism of the Oral Contraceptive 17α-E thynylestradiol-3-Methyl Ether (Mestranol) by Rat Liver Microsomes

Phenobarbitone Interaction With Oral Contraceptive Steroids in the Rabbit and Rat

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Demethylation of Mestranol to Ethinyloestradiol in Vitro and in Vivo

Cited by 24 publications

References 9 publications

Metabolism of Synthetic Steroids by Animals and Man

Metabolism of Synthetic Steroids by Animals and Man

Stimulatory Effect of Phenobarbital on the Metabolism of the Oral Contraceptive 17&alpha;-E thynylestradiol-3-Methyl Ether (Mestranol) by Rat Liver Microsomes

Phenobarbitone Interaction With Oral Contraceptive Steroids in the Rabbit and Rat

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Stimulatory Effect of Phenobarbital on the Metabolism of the Oral Contraceptive 17α-E thynylestradiol-3-Methyl Ether (Mestranol) by Rat Liver Microsomes