Stereoselective biotransformations of dl-norgestrel and its enantiomers in the African green monkey.

Abstract

The comparative metabolism of dl -, d -, and l -norgestrel was investigated in African Green Monkeys ( Cercopithecus aethiops ). Total 14C excretion in urine after a single oral dose of 14C- dl -norgestrel (1 mg/kg) was significantly higher (51.4 ± 5.0%) than that observed after administration of the d -enantiomer (37.5 ± 5.4%) but not the l -enantiomer (44.2 ± 8.9%). In all cases, the major part of the urinary radioactivity was present in a free fraction (48-62%), while an additional 13-27% was released by β-glucuronidase preparations. No sulfate conjugates were detected. At least one major (16β-hydroxylation) and one minor (16α-hydroxylation) metabolic pathway were stereoselective, i.e. , they are operative with the I -but not the d -enantiomer. Three metabolites, 16β-hydroxynorgestrel, 16α-hydroxynorgestrel, and 16-hydroxytetrahydronorgestrel (believed to be 16β) were only detected in urine samples obtained from 14C- dl and - l -norgestrel-dosed animals. Following 14C- d -norgestrel administration, 3α, 5β-tetrahydronorgestrel was found to be the major urinary metabolite. These observations are compared with those reported earlier on the urinary metabolites of dl -norgestrel in women.