Desolon Mechanism of Action

Pharmacology: Pharmacodynamics: Mode of Action: Combination hormonal contraceptives inhibit ovulation via a negative feedback mechanism on the hypothalamus, which alters the normal pattern of gonadotropin secretion of a follicle-stimulating hormone (FSH) and luteinizing hormone by the anterior pituitary. The follicular phase FSH and midcycle surge of gonadotropins are inhibited. In addition, combination hormonal contraceptives produce alterations in the genital tract, including changes in the cervical mucus, rendering it unfavorable for sperm penetration even if ovulation occurs. Changes in the endometrium may also occur, producing an unfavorable environment for nidation. Combination hormonal contraceptive drugs may alter the tubal transport of the ova through the fallopian tubes. Progestational agents may also alter sperm fertility.
Pharmacokinetics: Ethinyloestradiol: Absorption: Ethinyloestradiol (EE) is rapidly and completely absorbed from the intestine with an absorption half-life of 0.2-0.4 hours. After oral administration of 50 mcg EE, the plasma peak time was approximately 1-2 hours, whereas plasma peak height amounted to 0.12 ± 0.03 mcg/l and the area under curve to 1048 ± 247 pg/ml/h. With EE, a great inter- and intra-population variability of plasma levels has been reported. As a result of gut wall metabolism during absorption and the effect of first-pass metabolism, the absolute bioavailability of EE after single-dose administration is approx. 45%. The absolute bioavailability of EE calculated on the basis of repeated measurements after administration of DSG (desogestrel)/EE 150/30 mcg/d for 21 days is 74 ± 25%. The reason for this figure being higher than the average figure of 45% mentioned previously, probably has to do with the fact that the former figure is based on single-dose administration and single measurements. A possible explanation for the higher absolute bioavailability of EE upon repeated measurements could be an influence on hepatic enzyme systems.
Distribution: After absorption there is a rapid distribution of EE over the body, with a volume of distribution of 3.8 l/kg, whereas the distribution half-life amounts to 0.5-2.5 hrs. Plasma protein binding with EE and its metabolites is almost completely (± 95%), mainly to albumin.
Metabolism: EE is subject to a significant degree of presystemic conjugation in both the small bowel mucosa (the major metabolite being EE-3-sulphate) and the liver. EE escaping gut wall conjugation undergoes hepatic conjugation and phase I metabolism (oxidation, reduction or hydrolysis).
Sulphate and glucuronide conjugates of both EE (direct conjugates) and phase I metabolites, which are excreted in bile, can undergo hydrolysis by gut flora. Hydrolysis of the direct conjugates yields EE which can be reabsorbed, thus producing an enterohepatic circulation.
Whether the enterohepatic circulation of EE contributes significantly to plasma concentration and hence to therapeutic effect in most women is not known. The metabolic pathways of EE are of two general types, hydroxylation, being the principal route, and in addition, although to a very minor extent, modification of the ethinylgroup. The principal hydroxylated metabolites of EE are, in order of importance respectively, the catechol oestrogen 2-hydroxy(OH)-EE and the catechol 2-methoxy-EE, whereas in addition small amounts of both 6alpha-OH-EE and 16B-OH-EE have been identified. 2-OH-EE is further metabolised to chemically reactive metabolites, probably o-quinone/o-semi-quinones, which can bind irreversibly to protein.
Elimination: EE disappears from the plasma in an elimination phase with a half-life of 13-27 hours. The excretion of conjugates of EE and its metabolites is via the urine and with the faeces (ratio 1:1.5).
Reports on the time after which steady state conditions are reached reflect great differences: 3-4 days (no specific preparation mentioned); 7 days triphasic LNG (levonorgestrel)/EE; 10-13 days (DSG/EE 150/30 mcg/d).
Desogestrel: Absorption: After oral administration, desogestrel (DSG) is rapidly and almost completely absorbed (most probably from the duodenum), with an absorption half-life of 0.2 hours (range 0.1-0.4 h). During phase I metabolism DSG is almost completely converted in the body, mainly into the pharmacologically active metabolite 3-ketodesogestrel (3K-DSG). After oral administration of 150 mcg DSG + 30 mcg EE the plasma peak time of 3K-DSG was 1.8 ± 0.8 h whereas peak height amounted to 6.4 ± 3.7 mcg/l. The mean serum level of 3K-DSG 12 hours after dosing was 1.4 ± 0.5 mcg/l and the mean area under curve was 45.5 ± 24.4 mcg/h/l. There was, however, a great inter-individual variability of the plasma levels, a well-known phenomenon with progestagens.
Previously mentioned parameters point to a high first pass metabolism of DSG and indicate that the relative bioavailability of the agent is comparable to that of 3K-DSG. The absolute bioavailability of 3K-DSG after single dose administration is about 76 ± 23% and during steady-state conditions 81 ± 27%.
Distribution: The distribution half-life of 3K-DSG in women is ± 1.4 hours (range 1.1-1.8 hrs). Plasma protein binding of 3K-DSG and its metabolites in clinical and experimental studies is almost complete (98%), mainly to albumin.
Metabolism: Studies in female volunteers with radioactive-labelled desogestrel show that the compound is completely metabolized. Phase I metabolism (biotransformation), which is rapid, includes hydroxylation of the C3-atom, whereby 3-alpha and 3-beta hydroxy-DSG are formed, which are subsequently dehydrogenized into 3K-DSG. There is no indication for the biotransformation of the 11-methylene-group. Hydroxylation and dehydrogenation are normal metabolic processes in the liver. The rapid biotransformation indicates that this process does not constitute a burden to the liver. The active metabolite 3K-DSG is further reduced to 3-alpha-OH-5-alpha-H-DSG via 3K-5-alpha-H-DSG.
Subsequently, these degradation products are partly converted into polar metabolites by conjugation into sulphates and glucuronides. Enterohepatic circulation is not of importance for the progestagenic activity of desogestrel, since only some inactive metabolites undergo this pathway.
Elimination: 3K-DSG disappears from the plasma in an elimination phase with a half-life of 21 hrs (range 16-29 hrs). The excretion of DSG and its metabolites is via the urine and with the faeces, the ratio being 1.5:1. As a result of the pharmacokinetic properties of desogestrel, steady-state conditions (no further increase in plasma concentration) are reached within 10 days of daily administration. Based on both steady state and excretion data, it can be assumed that there is no accumulation of the drug in the body.