The trans-cis isomerization of trans-4′-(2-hydroxy 3,5-dibromo-benzylamino)cyclohexanol in vivo and in vitro in different species

Abstract

1. Isomerization of trans-4′-(2-hydroxy-3,5-dibromo-benzylamino)cyclohexanol (HDBC) in vivo has been investigated in horse, cow, dog, rat and man.

2. Following oral administration of 4′-trans-HDBC to the horse, a very efficient firstpass trans-cis isomerization was observed. In the urine of the horse and cow, 40% and 29% respectively of the conjugated alcohols consisted of the 4′-cis isomer. Isomerization in rat and dog took place only to a small extent, and in man no 4′-cis isomer was detected.

3. Oxidation of HDBC to the corresponding ketone, at pH 9.0, was highest with horse and rat-liver 10 000g supernatants and lowest with dog-liver supernatant.

4. Reduction of the ketone with 10 000g liver supernatants and with cryst. horse-liver alcohol dehydrogenase led to the formation of the alcohol containing 42–69% as the 4′-cis isomer, whereas after reduction with NaBH₄ the alcohol contained only 20% of the 4′-cis isomer. This indicates that the conformer with the lower energy (1′ and 4′ position equatorially substituted) preferentially formed only during chemical reduction.

5. A correlation between the formation of the ketone in vitro and the formation of 4′-cis-HDBC in vivo was observed in the horse, cow and dog. No similar correlation was found in the rat, where a high in vivo trans-cis isomerization might have been expected from the in vitro data.