Pharmacokinetics
The bioavailability of desogestrel has been found to range from 40 to 100%, with an average of 76%. This significant interindividual variability is comparable to that with norethisterone and levonorgestrel. Peak concentrations of etonogestrel occur about 1.5 hours after a dose while concentrations of desogestrel are very low and have disappeared by 3 hours after a dose. Steady-state levels of etonogestrel are achieved after about 8 to 10 days of daily administration. Accumulation of etonogestrel is thought to be related to progressive inhibition of 5α-reductase and cytochrome P450 monooxygenases (e.g., CYP3A4). The plasma protein binding of desogestrel is 99% and it is bound exclusively to albumin. Etonogestrel is bound 95 to 98% to plasma proteins. It is bound about 65 to 66% to albumin and 30 to 32% to SHBG, with 2 to 5% free in the circulation. While desogestrel is not bound to SHBG, etonogestrel has relatively high affinity for this plasma protein of 3 to 15% of that of dihydrotestosterone, although this is considerably less than that of the related progestins levonorgestrel and gestodene. Neither desogestrel nor etonogestrel are bound by corticosteroid-binding globulin.Desogestrel is a prodrug of etonogestrel (3-ketodesogestrel) and upon ingestion is rapidly and completely transformed into this metabolite in the intestines and liver. Hydroxylation of the C3 position of desogestrel catalyzed by cytochrome P450-dependent enzymes, with 3α-hydroxydesogestrel and 3β-hydroxydesogetrel as intermediates, followed by oxidation of the C3 hydroxyl group, is responsible for the transformation. A small percentage of desogestrel is metabolized into levonorgestrel, which involves the removal of the C11 methylene group.
The addition of a low dose of 50 or 100 mg/week intramuscular testosterone enanthate after 3 weeks increased testosterone levels and further suppressed LH and FSH levels, to the limits of assay detection (i.e., to undetectable or near-undetectable levels), in both the 150 μg/day and 300 μg/day desogestrel groups. Upon cessation of treatment, levels of LH, FSH, and testosterone all recovered to baseline values within 4 weeks. Androgenic activity
Etonogestrel has about 20% of the affinity of metribolone and 50% of the affinity of levonorgestrel for the androgen receptor (AR) while desogestrel has no affinity for this receptor. The 5α-reduced metabolite of etonogestrel, 5α-dihydroetonogestrel (3-keto-5α-dihydrodesogestrel), also has some affinity for the AR (about 17% of that of metribolone). Desogestrel (via etonogestrel) has very low androgenic potency, about 1.9 to 7.4% of that of methyltestosterone in animal assays, and hence is considered to be a very weak androgen. Although etonogestrel has about the same affinity for the AR as norethisterone, due to the relatively increased progestogenic potency and decreased androgenic activity of etonogestrel, the drug has markedly higher selectivity for the PR over the AR than older 19-nortestosterone progestins like norethisterone and levonorgestrel. Conversely, its selectivity for the PR over the AR is similar to other newer 19-nortestosterone progestins like gestodene and norgestimate. It has been estimated that 150 μg/day desogestrel has less than one-sixth of the androgenic effect of 1 mg/day norethisterone (these being common dosages of the drugs used in combined oral contraceptives).