The metabolism of 2,4-dibromo-17 alpha-ethynyl[6,7-3H]oestradiol in the rat.
1. The metabolism of 2,4-dibromoethynyloestradiol (2,4-DBEE2) in the rat was studied in order to determine the influence of ring-A substituents on the phase I biotransformations of oestrogens. 2. 2,4-Dibromo-17 alpha-ethynyl[6,7-3H]oestradiol was synthesized by the one-stage bromination of 17 alpha-ethynyl[6,7-3H]oestradiol (EE2) with N-bromoacetamide, and administered (30 micrograms/kg, i.v.) to anaesthetized male and female rats. 3. A single metabolite, identified as a glucuronide of 2,4-DBEE2, was rapidly and extensively eliminated in bile by male rats (83% of the dose over 6 h). Females excreted additional minor conjugated metabolites. Neither unchanged 2,4-DBEE2 nor EE2 was detected in bile. 4. The hepatic residues after 6 h (percentage of dose) were 2.7% and 3.4% in male and female rats, respectively, whilst less than 0.1% per organ(s) was found in kidneys, heart, spleen, lungs and brain. 5. 2,4-Dibromo substitution of EE2 effectively blocked all phase I biotransformations whilst not limiting glucuronylation in male rats, but did not entirely preclude phase I metabolism in females. The inertness of 2,4-DBEE2 to ring-A hydroxylation in male rats conforms with the insignificant debromination of 2,4-dibromoestradiol by hepatic microsomes.
Maggs
J L
JL
Department of Pharmacology and Therapeutics, University of Liverpool, U.K.
Morgan
P
P
Hussain
F
F
Page
P C
PC
Park
B K
BK
D000818:Animals; D001646:Bile / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D002851:Chromatography, High Pressure Liquid; D004958:Estradiol / Q000378:metabolism*; D004997:Ethinyl Estradiol / Q000031:analogs & derivatives*; D015946:Ethylene Dibromide / Q000378:metabolism*; D005260:Female; D006868:Hydrolysis; D008297:Male; D008657:Metabolic Clearance Rate; D051381:Rats; D011919:Rats, Inbred Strains; D015262:Xenobiotics
D015262:Xenobiotics; D015946:Ethylene Dibromide; D004997:Ethinyl Estradiol; D004958:Estradiol; C063266:2,4-dibromo-17-ethynyl(6,7)estradiol