Structure-metabolism relationships of ring-A halogenated analogues of 17 alpha-ethynyloestradiol.
The metabolic fates of 2-chloro-, 2-bromo-, 4-bromo- and 2-iodo-17 alpha-ethynyloestradiol (EE2) in rats were determined. 6,7-3H-labelled analogues (0.1-2.0 mumol/kg) were administered i.v. to anaesthetized animals. The metabolites of all four compounds were rapidly and extensively excreted in bile (79-93% of the dose over 6 h). Unlike EE2 and 2-fluoro-EE2 (2-FEE2), neither 2-chloro(Cl)-(2.0 mumol/kg),2-bromo(Br)-(0.1 mumol/kg), nor 2-iodo(I)-EE2-(0.1 mumol/kg) underwent C-2 hydroxylation in female rats; 2-BrEE2 was similarly refractory in male rats; females, was subject to approx. 2-fold greater C-2 hydroxylation than 2-FEE2 but this equalled only approx. 60% of that undergone by EE2. All three of the C-2 halogenated derivatives were substantially excreted unchanged except for conjugation. 2-ClEE2 alone was C-4 hydroxylated to an appreciable extent. The oxidative metabolism of 2- and 4-BrEE2 in rats was sexually differentiated: 2-BrEE2 yielded an alkyl hydroxylated metabolite and a two-component dihydroxylated fraction in the ratio 1:0.09 and 1:0.76 in males and females, respectively; 4-BrEE2 underwent C-2 and alicyclic (C-15) hydroxylation in the ratio 1:4.8 and 1:0.07 in males and females, respectively. 2-ClEE2 formed much less alkyl monohydroxylated metabolite (C-16 hydroxylated for 2-Cl- and 2-IEE2) than did either 2-BrEE2 or 2-IEE2. The observed structure-metabolism relationships are discussed.
Bonham
N M
NM
Department of Pharmacology and Therapeutics, University of Liverpool, England.
Maggs
J L
JL
Bulman-Page
P C
PC
Park
B K
BK
D000818:Animals; D001646:Bile / Q000378:metabolism; D001966:Bromine; D002713:Chlorine; D004997:Ethinyl Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D005260:Female; D006219:Halogens; D006900:Hydroxylation; D007455:Iodine; D007700:Kinetics; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics; D013329:Structure-Activity Relationship; D014316:Tritium
D006219:Halogens; D014316:Tritium; D004997:Ethinyl Estradiol; D002713:Chlorine; D007455:Iodine; D001966:Bromine