N-demethylation ofethylmorphine inpregnantandnon- pregnant women andinmen: an evaluation oftheeffects ofsex steroids

1 Theeffects ofoestrogens, testosterone, progesterone andmedroxyprogesterone acetate (MPA)on therateofN-demethylation ofethylmorphine (EM)tonorethylmorphine (NEM)were studied inhumanadult liver microsomes. 2 N-Demethylase activity was found tobeinhibited byprogesterone andMPA toa similar extent while oestrogens andtestosterone hadno ornegligible effects. 3 Thesefindings prompted us tomeasure theN-demethylation ofEM inrelation to serum progesterone concentration invivointhree groupsofvolunteers withlarge physiological differences intheir endogenous levels ofprogesterone, i.e. i)pregnant women, ii) non-pregnant ovulating women andiii) men. 4 Themetabolic ratio (MRp)ofEM toNEM inplasma 60minafter dosage andthe corresponding ratio inurine sampled for6h(MRu1), measured on twooccasions 14 daysapart were usedtoreflect intraindividual variation intherateofN-demethylation. 5 Theaveragedifference inMRpandMRu,1between thetwooccasions wassimilar in all groups.However, thevariability inMRpbetween individuals within a groupwas significantly higher inovulating women thaninmen, butthis hadno relation tothe serumconcentrations ofprogesterone oroestradiol. 6 Thecumulative 12h urinary excretion ofEM,NEM andmorphine (MO)after hydrolysis with,-glucuronidase was about46%.Therewas no difference inthe metabolic ratio ofEM toNEM anditsconjugate(s) intheurine between theluteal and thefollicular phases. Ourfindings suggest that themenstrual cycle doesnotinfluence therateofN-demethylation ofEM.