DESCRIPTION Primobolan® oral tablets contain 100 mg of the chemically described as 4-Androsten-4-ol -3beta ,17beta-dione Acetate an irreversible, steroidal aromatase inhibitor. Chemical Structure Its molecular formula is C21 H28-04 The active ingredient is a white crystalline powder with a molecular weight of 344.4 Each Tablet contains the following: Inactive ingredients: Magnesium Carbonate, Microcrystalline Cellulose, Pregelatinized Starch, Stearic Acid, Magnesium Stearate, and Croscramellose Sodium. CLINICAL PHARMACOLOGY The chemical term 4-Androstenoldione Acetate refers to the isomer: 4-Androsten-4-ol-3beta,17beta-dione Acetate. 4-Androstenoldione Acetate is the acetate ester derivative of 4-Hydroxy-4-Androstenedione, which is an analog or derivative of the naturally occurring precursor hormone 4-Androstenedione. 1 This compound concerns the isomer form of 4Androsten-4-ol-3beta,17beta-dione Acetate. 4-Androstenoldione Acetate is a steroidal aromatase inhibitor that inhibits estrogen biosynthesis, increases natural production of total and free testosterone, and may inhibit DHT formation. It does this by inhibiting the Cytochrone P-450 enzyme, which converts testosterone to estrogen. Once estrogen levels fall a signal is sent to the hypothalamic pituitary axis to produce (LH) luteinizing hormone and decrease (SHBG) steroid hormone binding globulin. 2 ,3 LH then stimulates the testes to increase total testosterone production, in which a large portion is free or active testosterone due to the decrease in SHBG. This increased amount of testosterone is then metabolized with less estrogen and DHT conversion.4 Metabolic Actions Compounds in this class also may cause retention of nitrogen, sodium, potassium, and phosphorous, and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when there is sufficient intake of calories and protein. Androgens have been reported to stimulate production of red blood cells by enhancing production of erythropoietic stimulation factor. Pharmacokinetics The compound is mainly eliminated by metabolism, renal excretion of metabolites accounting for 95% of dose. The excretory balance of 14C-compounds in urine and feces totals up to 98.9+/-0.8% of the i.v. dose after 168 h. The 14C-compounds in plasma and urine were separated by HPLC, and three major metabolites were submitted to structural analysis by MS, NMR and UV spectroscopy. One of the metabolites is the direct 4-O-glucuronide of formestane. The other two represent 3-O-sulfates of the exocons 3beta,4beta-dihydroxy-5alpha-androstane-17-one and 3alpha,4beta-dihydroxy-5alpha-androstane-17-one, their ratio being 7:3. These exocons are formed by stereoselective 3-keto reduction, accompanied by reduction of the 4,5-enol function. The exocons do not inhibit human placental aromatase activity in vitro. 5 The half-life orally was approximately 3 h, whereas the apparent half-life of injected drug was between 5 and 10 days after a more rapid clearance during the first 4 days after injection. The formulated material achieved a significantly higher mean peak concentration (88% greater than that obtained using the unformulated powder) and a higher mean AUC (not significant). The median time to peak was 1.5 h for both preparations and the elimination rate constants were similar (0.31 for micronized 4-OHA and 0.36 h-1 for formulated 4-OHA). Significant biological activity was demonstrated with the formulated material in its suppression of plasma oestradiol levels. 6 Efficacy Studies Subcutaneous treatment of immature male rats with an estrogen precursor, 19-hydroxy-testosterone (19-OHT), at a daily dose of 1 mg/animal for 14 days leads to a significant decrease in the weight of testis, ventral prostate and seminal vesicle. The peripheral levels of LH are lowered. Testicular histology indicates that the effects of 19-OHT are very similar to the known of effect induced by estradiol-17 beta. 19OHT induces a marked impairment of spermato and spermiogenesis. The maturation division is completely inhibited. The effect of 19-OHT on spermatogenesis is partially reversed by concomitant administration of an aromatase inhibitor (4-acetoxy-4-androstene-3.17-dione, (4-AA] at a dose of 1 mg/animal/day s.c. Meiotic activity is restored, and the weights of genital organs and the serum LH values increase. 4-AA alone has no appreciable effect on the parameters examined in this study. The present results suggest that specific inhibitors of estrogen biosynthesis might not only be useful to investigate the patho-physiological role of estrogens on spermatogenesis. 7 Clinical Studies Another interesting note is the ability of 4-Androsten-4-ol-3, 17-dione acetate to directly stimulate testosterone whether in the presence of LH or not. Researchers examined the effects of placebo, luteinizing hormone (LH), 4-acetoxy-4-androstenedione, and luteinizing hormone (LH) plus 4-acetoxy-4-androstenedione on rat follicles in vitro. In regards to testosterone they found that within the first 8 hours 4-acetoxy-4-androstenedione had the ability to directly stimulate testosterone alone and greatly stimulate testosterone in combination with luteinizing hormone (LH). Interestingly enough within the next 16 hours they discovered 4-acetoxy-4-androstenedione alone was stimulating testosterone 3 times as much as luteinizing hormone (LH) while the combination also continued to stimulate testosterone |