Enhanced Oral Bioavailability of Chlormadinone Acetate through a Self-Microemulsifying Drug Delivery System for a Potential Dose Reduction.

Chlormadinone acetate (CMA) is a derivative of the naturally secreted hormone progesterone and exhibits reliable contraceptive and non-contraceptive benefits. Although the marketed product of CMA as oral tablets under the trade name Belara® has been highly successful, there is still room for further improvements in oral bioavailability and a reduction in the clinical dose to decrease related adverse effects. In the current study, a CMA-based self-microemulsifying drug delivery system (SMEDDS) was developed using 32% ethyl oleate as an oil phase, 40% Tween-80 as a surfactant, and 12% Transcutol P combined with 16% PEG400 as a cosurfactant, resulting in spherical droplets with a z-average particle size of 38.92 nm and an average zeta potential of - 3.18 mv. The in vitro release rate of CMA from CMA-SMEDDS in different media (distilled water, HCl solution at pH 1.2, phosphate buffers at pH 4.5 and pH 6.8) was significantly faster than that from Belara® in the first 15 min. A pharmacokinetic study in rats showed that the Cmax and AUC of CMA-SMEDDS were significantly higher (P < 0.01) than those of Belara®, with a 1.98-fold increase in oral bioavailability. In comparison with Belara®, the developed CMA-SMEDDS showed promising release profiles both in vitro and in vivo, which could potentially be useful in enhancing oral bioavailability and reducing the clinical dose of CMA.

Metabolism of osaterone acetate in dogs and humans.

Osaterone acetate (17 alpha-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione; OA) is a steroidal antiandrogen. In order to clarify the species differences, metabolites of OA were examined in plasma, urine, and feces of dogs and humans after oral administration of OA. Eleven metabolites in plasma, urine, and feces were identified by their spectral properties and comparison to appropriate standards. The primary routes of OA metabolism involve 11 beta-, 15 beta- and 21-hydroxylation, 17 alpha-deacetylation, and dechlorination. Other metabolites arise from combinations of these pathways to form multiple oxidized metabolites. All metabolites observed in humans occurred in dogs. 11 beta-Hydroxylated metabolites (11 beta-OH OA and 11-oxo OA) were found in the plasma and urine of dogs, but there was no evidence of their presence in humans. 11 beta-Hydroxylation of exogenous steroids represents a distinctive biotransformation pathway.

Pharmacokinetics and biliary excretion of osaterone acetate, a new steroidal antiandrogen, in dogs.

The pharmacokinetics and biliary excretion of osaterone acetate (17alpha-acetoxy-6-chloro-2-oxa-4,6-pregnadiene-3,20-dione; OA), a new steroidal antiandrogen, were investigated in intact dogs and biliary fistula dogs after bolus intravenous administration of (14)C-labeled drug. In intact dogs, OA exhibited a biexponential disposition with a very long half-life of 197.9 +/- 109.9 h. OA accounted for almost all the plasma radioactivity. The major route of excretion was in feces via the bile. One-third of the radioactivity in the bile was due to OA. The major biliary metabolite was identified as a glucuronide of 17alpha-acetoxy-6-chloro-21-hydroxy-2-oxa-4,6-pregnadiene-3,20-dione. A significant amount of biliary recycling occurs in dogs.

Evidence that chlormadinone acetate exhibits antiandrogenic activity in androgen-dependent cell line.

Chlormadinone acetate (CMA), like other 17-hydroxyprogesterone derivatives, is thought to be a potential antiandrogen on the basis of its effect on spontaneous benign prostatic hyperplasia (BPH) in dogs. This work was undertaken to find out whether CMA presents antiandrogen activity in human androgen-dependent cell line. For this purpose, we used PALM cells, the PC-3 cell line stably transfected with human androgen receptor and a luciferase gene under transcriptional control of MMTV. Potential antiandrogenic activity was compared with that of cyproterone acetate (CPA), a standard steroidal antiandrogen. Both compounds were tested in competitive binding assays at 37 degrees C in the presence of 1 nM of [3H] R1881, a synthetic and non-metabolizable androgen. Their impact on AR transcriptional activity was evaluated by the measure of luciferase activity in the presence of R1881 with increasing concentrations of CMA or CPA (10(-8)-10(-6) M). In whole cell binding assays, competitive studies revealed that the Ki for CMA was 3.3 +/- 1.5 x 10(-8) M (versus 7.2 +/- 1.3 x 10(-8) M for CPA). Inhibition of AR transcriptional activity was 40 +/- 5% for CMA (3 x 10(-7) M) versus 59 +/- 6% for CPA at the same concentration. Moreover, CMA caused a slower import of green fluorescent protein (GFP)-AR to the nuclei of COS-7 cells than R1881. These data show that CMA exerted a competitive binding for AR and significantly decreased the AR transcriptional activity. In conclusion, this synthetic progestin presents simultaneous antiandrogenic activity that could be helpful as a new therapeutic option in women with luteal defect along with clinical signs of hyperandrogenism.

In vitro binding of progesterone to receptors in the human endometrium and the myometrium.

High affinity, low capacity progesterone binding receptors have been identified in the cytosol fractions of the human endometrium and the myometrium. The endometrial and the myometrial progesterone binding proteins had sedimentation coefficients of 4.5 S and 4.1 S, respectively. Analysis of the bound steroids revealed that, along with progesterone, small amounts of its metabolites (20alpha-hydroxy-4-pregnene-3-one, 5alpha-pregnane-3,20-dione, 5alpha-pregnane-20alpha-ol-3-one) were also bound to the receptor proteins. Among the steroids studied for ligand specificity, 5alpha-pregnane-3,20-dione showed the highest competition for progesterone binding sites. Progestational steroids, like chlormadinone acetate and norgestrel, did not compete for the progesterone receptors. The endometrial and the myometrial progesterone binding receptors were thermolabile and protein in nature. The molecular weight of the endometrial progestrone binding protein was about 60,000-67,000 with a molecular (Stokes) radius of 33 A and the frictional ratio of 1.26. The myometrial progesterone binding protein had a molecular weight of 56,000-58,000 with a molecular (Stokes) radius of 31 A and a frictional ratio of 1.23. The binding of corticosterone to the myometrial cytosol was only 22-34%, whereas with progesterone it was 70-95%. A study of the immunoabsorption of the plasma proteins from the endometrial and the myometrial cytosol suggested the presence of specific progesterone binding receptors in the cytosol that were different to plasma proteins. The association constant of progesterone for the endometrial progesterone receptor was 1.9 x 10(9) M(-1) and for the myometrial progesterone receptor it was 1.4 x 10(9) M(-1), values that are higher than the association constant of progesterone for corticosteroid binding globulin, which is 7 x 10(8) M(-1). The evidence suggested that the human endometrial and the myometrial progesterone binding proteins are different to the corticosteroid-binding globulin.