The metabolism of 2,4-dibromo-17α-ethynyl[6,7-³H]oestradiol in the rat

Abstract

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-17α-ethynyl[6,7-³H]oestradiol was synthesized by the one-stage bromination of 17α-ethynyl[6,7-³H]oestradiol (EE₂) with N-bromoacetamide, and administered (30 μg/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 <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.