Metabolism and Tissue Distribution of Norethisterone and Norgestrel in Rabbits

Abstract

After injection of [4-14C]norethisterone or norgestrel labelled with 14C in the ethynyl group into rabbits, 45 % and 57\m=.\4% of the radioactivity was excreted in the urine, mostly within 2 days. Although small amounts of radioactivity were excreted in the expired air of rabbits receiving norgestrel, little metabolism of the ethynyl group occurred. Radioactivity in plasma declined quickly after injection and 24 hr. later less than 0\m=.\5 % of the dose remained in the circulation. Up to 5 hr. after injection large amounts of radioactivity were found in liver, kidney, intestine and bile; a large proportion of the dose appeared to undergo an entero-hepatic circulation. Although the concentration in fat and muscle was low the total amount in these tissues may approach 5%. The uterus contained a high concentration of radioactivity suggesting that this tissue may bind the progestins or their metabolites. By 24 hr. the amount of radioactivity in the tissues had markedly decreased. Small amounts of radioactivity crossed the placenta of pregnant animals near term and small amounts were found in the foetus and amniotic fluid. Within 3 hr. of the injection at least half of the radioactivity in the tissues was in a conjugated form and considerable metabolism of the injected progestins had occurred. Little, if any, norethisterone or norgestrel was present in the tissues. The metabolites of norethisterone were mainly polar compounds showing that hydroxylation of the steroid had occurred, whereas the metabolites of norgestrel appeared to be similar to the compounds produced by partial or complete reduction of the \g=a\,\g=b\-unsaturated ketone grouping in ring A.

Metabolism of [14c]norgestrel in Man

“…Subject M 3 received 1 pc [14C]norgestrel adsorbed on to lactose in a gelatine capsule orally. The details of the investiga¬ tions together with the methods used for the estimation of radioactivity in urine and blood have been described previously (Kamyab, Littleton & Fotherby, 1967;Kamyab, Fotherby & Klopper, 1968a). For the isolation and identification of norgestrel metabolites, urine from subject M 2 was pooled and extracted in 11. quantities.…”

Metabolism of Synthetic Steroids by Animals and Man

“…When the bile duct of the animal was cannulated urinary excretion was reduced and 26-41% of the dose was found in bile. Using norethisterone or norgestrel, Kamyab et al (1967) found about half of the dose was excreted in the urine during a 7 day period with up to 5 % in the faeces. Some of the dose was excreted rapidly, as much as one quarter being found in the urine of some animals within 4 to 5 h of injection.…”

Plasma concentrations of ethynyl oestradiol and norethindrone after oral administration to women

“…Studies on the metabolism of these compounds in women have demon¬ strated that the ethynyl group in norethindrone remains intact (Kamyab, Fotherby & Littleton, 1967 ; Kamyab, Fotherby & Klopper, 1968 ;Fotherby, 1974), but that the ring A is transformed into several reduced products, i.e. 17rz-ethynyl-17ß-hydroxy-5a-oestran-3-one and 17ct-ethynyl-5a-oestrane-3ß,17ß-diol (Murata, 1968), 17o>ethynyl-5a-oestrane-3a,17ß-diol and 17a-ethynyl-5ß-oestrane3a,17ß-diol (Gerhards, Hecker, Hitze, Nieuweboer & Bellmann, 1971 ; Stillwell, Horning, Horning, Stillwell & Zlatkis, 1972).…”