Metabolism of the contraceptive steroid desogestrel by the intestinal mucosa.
1. The intestinal mucosal metabolism of the progestogen oral contraceptive desogestrel (Dg) has been studied in vitro using the Ussing chamber technique. Histologically normal ileum or colon was obtained from eight patients undergoing various resections. The mucosal sheets were mounted between two perspex chambers. 2. Two hours after addition of [3H]-Dg (0.2 microCi; 100 ng) to the mucosal chamber, more than 90% of the steroid was present in that chamber. In studies with colon, metabolite analysis showed that 55.4 +/- 11.7% (mean +/- s.d.; n = 6) of drug present was Dg, 28.9 +/- 11.4% as unconjugated Phase I metabolites, 13.3 +/- 2.6% as sulphate conjugates and 2.5 +/- 1.5% as glucuronide conjugates. 3. By co-chromatography with authentic metabolites and mass spectrometry, it was shown that 3-keto desogestrel is formed in the mucosa. This is the active metabolite of desogestrel. A large peak of radioactivity did not co-chromatograph with any known metabolites and has been tentatively identified as ring hydroxylated products of 3-keto desogestrel. 4. The effect of the synthetic oestrogen ethinyloestradiol (EE2) on the metabolite profile of Dg was studied. In the presence of increasing concentrations of EE2 (100 ng, 1 and 10 micrograms), there was competition for sulphation such that the sulphate fraction decreased by 32, 49 and 48% respectively. 5. The results of this study indicate substantial first pass metabolism of desogestrel by the gut mucosa with evidence for the formation of the active metabolite. The extent of phase I metabolism is unusual.
Madden
S
S
Department of Pharmacology and Therapeutics, University of Liverpool.
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D J
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Martin
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Orme
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D002851:Chromatography, High Pressure Liquid; D017135:Desogestrel; D004997:Ethinyl Estradiol / Q000494:pharmacology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D009652:Norpregnenes / Q000378:metabolism*
D009652:Norpregnenes; D004997:Ethinyl Estradiol; D017135:Desogestrel