ZUM STOFFWECHSEL VON NORETHISTERON (17α-ÄTHINYL-4-ÖSTREN-17β-OL-3-ON) UND DL- SOWIE D-NORGESTREL (18-METHYL-17α-ÄTHINYL-4-ÖSTREN-17β-OL-3-ON) BEIM MENSCHEN
Authors: Gerhards E. , Hecker W. , Hitze H. , Nieuweboer B. , Bellmann O. 
Published: December 2008

The metabolism of norethisterone (17α-ethinyl-4-oestren-17β-ol-3-one) and of DL- and D-norgestrel (13-ethyl-17α-ethinyl-4-oestren-17β-ol-3-one) was investigated in man.

Two hours after oral administration 0.25 mg of [3H]-norethisterone produced a maximum 3H-plasma level of 2 μg/100 ml calculated as norethisterone. During the first 24 hours, the 3H-concentration in the plasma fell to 15% of the maximum.

Two hours after oral administration of 0.25 mg of [3H]-D-norgestrel, the radioactivity maximum in the plasma was in the region of 1 μg/100 ml, calculated as norgestrel

During the first 7 hours after the oral administration of 0.25 mg of [3H]-D-norgestrel, 50–75 % of the radioactive compounds in the plasma were freely extractable, whereas after administration of 0.25 mg of [3H] -norethisterone there were only 20–30 % free extractable. Similarly, 48 and 72 hours after administration of D-norgestrel, the proportion of nonconjugated compounds in the plasma (about 35 %) was markedly higher than after administration of norethisterone. In the latter case, about 20 % were still freely extractable after 48 and 72 hours. Both after administration of norgestrel and norethisterone, 80–95 % of the radioactive conjugates in the plasma consisted of sulphuric acid esters, of which, however, only a small number were cleavable by sulphatase.

The concentration of unchanged norethisterone in the plasma decreased much more rapidly than that of unchanged norgestrel. 24 hours after oral administration of 0.25 mg of norethisterone, no more unchanged compound was detectable in the plasma. On the other hand, 24 hours after oral administration of 0.25 mg of D-norgestrel, 30% of the freely extractable compounds were unchanged norgestrel.

About one hour after oral administration of 0.25 mg of norethisterone, the maximum concentration of unchanged norethisterone in the plasma was 0.2 μg/100 ml. This concentration declined rapidly; after 4 hours it was 0.05 μg/100 ml and after 7 hours only 0.02 μg/100 ml.

The maximum concentration of free norgestrel in the plasma was about 0.3 μg/100 ml after one hour, about 0.15 μg/100 ml after 4 hours, 0.08 μg/100 ml after 7 hours, and 0.04 μg/100 ml after 24 hours. After oral administration of norethisterone, the following ring A-reduced metabolites were detectable in the plasma in the glucuronoside fraction: 17α-ethinyl-5β-H-3α,17β-diol, 17α-ehinyl-5β-H-3β,17β-diol and 17α-ethinyl-5α-H-3α,17β-diol. After sulphatase cleavage, the only metabolite of norethisterone detectable in the plasma was 17-α-ethinyl-5β-H-3β,17β-diol.

After administration of norethisterone, about 40–50 % of the dose was excreted with the urine, about 30–40 % in the first three days.

After administration of DL-norgestrel, about 60 % of the dose was eliminated with the urine in 3 days. About 20–40 % of the dose was excreted with the faeces after administration of norethisterone and norgestrel. With both compounds, sulphates (about 50–65 %) were predominant in the conjugate fraction of the urine. 17α-ethynyl-5β-oestrane-3α,17β-diol was detected and identified as the main metabolite of norethisterone in the glucuronoside fraction of the urine. This metabolite accounted for 25–28 % of compounds that could be extracted from the urine after glucuronidase cleavage. 17α-ethinyl-5α-oestrane-3α,17β-diol was another metabolite of norethisterone which was identified in the glucuronoside fraction. In addition to these two metabolites, the compounds 17α-ethinyl-5α-oestrane-3β-diol and 17α-ethinyl-5β-oestrane-3β,17β-diol, which only occur in small amounts, were detected in the urine.

In the case of compounds that were extractable after sulphatase cleavage, 17α-ethinyl-5β-oestrane-3β,17β-diol was identified as the main metabolite of norethisterone.

After administration of norgestrel, the main metabolite occurring in the glucuronoside fraction of the urine was, as with norethisterone, the compound which was reduced to 5β-H-3α-ol. This metabolite (13β-ethyl-17α-ethinyl-5β-oestrane-3α,17β-diol) accounted for about 15–50 % of the radioactivity of glucuronoside fraction. In addition, small amounts of 13β-ehtyl-17α-ethinyl-5β-oestrane,3β,17β-diol could be detected as metabolite. In metabolism norethisterone and norgestrel exhibit a qualitatively similar or like behaviour. The main difference is the inhibition of ring A reduction with norgestrel, which is also demonstrable in vitro with liver tissue of female rats. Obviously, the more potent biological action of norgestrel – compared with norethisterone – can be attributed, at least partly, to the inhibition of ring A-reduction, due to which the unchanged compound remains longer in the organism.