DEMETHYLATION OF MESTRANOL TO ETHINYLOESTRADIOL IN VITRO AND IN VIVO

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Abstract
The present concept is that mestranol must be demethylated to ethinyl-oestradiol in order to have oestrogenic activity. This activation of mestranol has been studied in vivo by means of radiospirometry and in vitro incubations with rat liver microsomes. During the microsomal incubation of doubly labelled [4-14C] mestranol and [3H-methoxy] mestranol with an NADPH-regenerating system 14C-labelled ethinyloestradiol was formed as the main metabolite, which was identified by crystallization to constant specific activity. In addition, a minor metabolite was found, which had the unaltered methoxy group. The enzymatic reaction was complete after 20 min. Pre-treatment of the rats with phenobarbital caused a threefold increase in ethinyloestradiol production. The in vivo results after application of mestranol tritiated in the methoxy group show an increase of the body water specific activity up to a maximum on the 2nd day. In the control rats 34.5% and in phenobarbital pre-treated rats 47.7% of the tritium was metabolized to body water. DDT-pre-treatment caused a HTO production of 60%. These values represent a minimal demethylation rate for the in vivo conditions.

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