STRUCTURE-METABOLISM RELATIONSHIPS RING-A HALOGENATED ANALOGS OF 17-ALPHA-ETHYNYLOESTRADIOL

The metabolic fates of 2-chloro-, 2-bromo-, 4-bromo- and 2-iodo-17 alp ha-ethynyloestradiol (EE,) in rats were determined. 6,7-H-3-labelled a nalogues (0.1-2.0 mu mol/kg) were administered i.v. to anaesthetized a nimals. The metabolites of all four compounds were rapidly and extensi vely excreted in bile (79-93% of the dose over 6 h). Unlike EE(2), and 2-fluoro-EE(2) (2-FEE(2)), neither 2-chloro(Cl)-(2.0 mu mol/kg),2-bro mo(Br)-(0.1 mu mol/kg), nor 2-iodo(I)-EE(2)-(0.1 mu mol/kg) underwent C-2 hydroxylation in female rats; 2-BrEE(2) was similarly refractory i n male rats; 4-BrEE(2)(0.1 mu mol/kg), in females, was subject to appr ox. 2-fold greater C-2 hydroxylation than 2-FEE, but this equalled onl y approx. 60% of that undergone by EE(2). All three of the C-2 halogen ated derivatives were substantially excreted unchanged except for conj ugation. 2-C1EE(2) alone was C-4 hydroxylated to an appreciable extent . The oxidative metabolism of 2- and 4-BrEE(2) in rats was sexually di fferentiated: 2-BrEE, yielded an alkyl hydroxylated metabolite and a t wo-component dihydroxylated fraction in the ratio 1:0.09 and 1:0.76 in males and females, respectively; 4-BrEE(2) underwent C-2 and alicycli c (C-15) hydroxylation in the ratio 1:4.8 and 1:0.07 in males and fema les, respectively. 2-C1EE, formed much less alkyl monohydroxylated met abolite (C-16 hydroxylated for 2-C1- and 2-IEE(2)) than did either 2-B rEE(2) or 2-IEE(2). The observed structure-metabolism relationships ar e discussed.