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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 norgestrelDuring 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 vitrowith 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.

The metabolism of 6α-fluoro-16α-methyl-pregna-1,4-diene-11β,21-diol-3,20-dione (fluocortolone) was investigated in 11 healthy volunteers.Following the intravenous injection of 1.7 mg [3H] -fluocortolone, the total 3H-activity in the plasma decreased by a half-life time of about four hours (Fig. 1). In the same test, the concentration of unchanged fluocortolone in the plasma decreased much more rapidly, with a first half-life period of about 50 minutes (Fig. 2).After oral administration of 20 mg [3H]-fluocortolone, two hours elapsed until maximum 3H-activity in the plasma was reached. The maximum 3H-concentration in the plasma, calculated as fluocortolone, was about 40–55 μg/100 ml. About 40–60% of the radioactivity was free extractable. During the first two hours after administration, the proportion of free extractable radioactive compounds in the plasma was approximately 70–90 % of the total 3H-activity. Most of the free extractable compounds were unaltered fluocortolone and only a few per cent consisted of 11-keto-fluocortolone. After oral administration of 20 mg fluocortolone the concentration of the unchanged compound in the plasma was about 10–30 μg/100 ml from the first to the sixth hour (Fig. 3a–d).In the first six hours after the oral administration of 20 mg fluocortolone, 50–90 % of the conjugated radioactive compounds in the plasma were present in the form of glucuronosides and 10–20% in the form of sulphates. The glucuronoside fraction could be split quantitatively by β-glucuronidase. After enzymatic hydrolysis the chromatographic behaviour of the extracted compounds was for the most part like that of unchanged fluocortolone. After sulphatase splitting of the plasma sulphate fraction no unchanged fluocortolone was detectable.The bound: free quotient as determined in human plasma by equilibrium dialysis showed a very similar qualitative course for fluocortolone and cortisol dependent on the corticoid concentration. With high corticoid concentrations, the quotient was 7–8 for fluocortolone and 2–3 for cortisol. In the physiological or therapeutic concentration range, the quotient for both compounds increased sharply with a decreasing steroid concentration.3H-elimination in the urine was examined after oral administration of 10, 20, 60 and 90 mg and after intravenous injection of 1.7 mg ([3H]-fluocortolone. Sixty-three to seventy-four per cent of the dose was eliminated in the urine within three days after 1.7 mg given intravenously and 10 mg administered orally. After oral doses of 20, 60 and 90 mg [3H] -fluocortolone, the 3H-elimination in the urine was 37–65% of the given dose during a three-day period. Individual fluctuations in 3H-elimination in the urine are so great that it is impossible to correlate the elimination velocity to the steroid dose administered. By far the greatest part of the total 3H-activity eliminated in the urine was excreted during the first 24 hours after oral and the first 12 hours after intravenous administration.Following oral administration of 10 and 90 mg [3H] -fluocortolone, about 10–30 % of the dose was eliminated in the faeces and after an intravenous administration of 1.7 mg the rate was 16%About 10–25 % of the radioactive compounds eliminated in the urine were present in nonconjugated form. In the oral test 41–65% of the radioactive compounds eliminated in the urine consisted of glucuronosides and in the intravenous test 85 % were glucuronosides. After splitting with sulphatase, only 3–7 % of the radioactive compounds present in the urine could be extracted.One fluocortolone metabolite in the conjugate fraction exhibited electrophoretic behaviour similar to that of steroid monosulphate. After separation of the »electrophoretic sulphate fraction« by thin-layer chromatography, approximately half of the »sulphates« consisted of fluocortolone21-carbonic acid.More than 90 % of the compounds eliminated in the urine in the form of free extractable steroids were identified. About 50 % of these compounds were identified as δ1-6β-ol-16α-methyl-corticosterone (compound C, Fig. 11). With 25–30%, the corresponding compound reduced in C20was the second main metabolite in this fraction of free extractable compounds (compound A, Fig. 11). The 11-ketones corresponding to these two main metabolites were present in about the same proportion, i.e. about 8% of the nonconjugated compounds (compounds B and D, Fig. 11).In all of the nonconjugated fluocortolone metabolites isolated and identified in the urine, the fluorine atom in the 6α position was eliminated by the introduction of a 6β-hydroxyl group. Despite the presence of the 16α-methyl group, the 20-keto group of fluocortolone can be reduced in vivo(compounds A and B, Fig. 11). It was not possible to determine whether 20α- or 20β-ole compounds result.Fifty-seven per cent of the fluocortolone metabolites eliminated in the urine as glucuronosides were identified (compounds E, F and G, Fig. 12). Fluorine was not split off in these compounds. Ring A is reduced in compound E (Fig. 12).The fluocortolone metabolites characterized as steroid sulphates on the basis of electrophoretic and thin-layer chromatographic behaviour could be split quantitatively by sulphatase and solvolysis. Following hydrolysis, in addition to higher polar compounds, the sulphate fraction was seen to contain only fluocortolone (Fig. 13). Unchanged fluocortolone is eliminated in the urine in the form of glucuronic acid and sulphuric acid conjugates.In addition to the glucuronic acid and sulphuric acid conjugates, fluocortolone-21-carbonic acid was isolated from the urine as a water-soluble metabolite (compound I, Fig. 13).After the oral administration of 20 mg fluocortolone, about 10% of the dose was found in the urine as dehalogenated metabolites within the first 24 hours. About 100 μg fluoride ions would therefore appear in the dehalogenation process during the 24-hour period. The fluoride quantity that may be expected in connection with fluocortolone administration is far below the fluorosis threshold concentration.