Pharmacodynamics Abiraterone, the active metabolite of<unk> . Antiandrogenic activity Abiraterone, the active metabolite of<unk> , inhibits CYP17A1, which manifests as two enzymes, 17α-hydroxylase ( = 2.5 nM) and 17,20-lyase ( = 15 nM) (approximately 6-fold more selective for inhibition of 17α-hydroxylase over 17,20-lyase) that are expressed in testicular, adrenal, and prostatic tumor tissues. CYP17A1 catalyzes two sequential reactions: (a) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by its 17α-hydroxylase activity, and (b) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by its 17,20-lyase activity. DHEA and androstenedione are androgens and precursors of testosterone. Inhibition of CYP17A1 activity by<unk>  thus decreases circulating levels of androgens such as DHEA, testosterone, and dihydrotestosterone (DHT).<unk> , via abiraterone, has the capacity to lower circulating testosterone levels to less than 1 ng/dL (i.e., undetectable) when added to castration. These concentrations are considerably lower than those achieved by castration alone (~20 ng/dL). The addition of<unk>  to castration was found to reduce levels of DHT by 85%, DHEA by 97 to 98%, and androstenedione by 77 to 78% relative to castration alone. In accordance with its antiandrogenic action,<unk>  decreases the weights of the prostate gland, seminal vesicles, and testes. Abiraterone also acts as a partial antagonist of the androgen receptor (AR), and as an inhibitor of the enzymes 3β-hydroxysteroid dehydrogenase (3β-HSD), CYP11B1 (steroid 11β-hydroxylase), CYP21A2 (Steroid 21-hydroxylase), and other CYP450s (e.g., CYP1A2, CYP2C9, and CYP3A4). In addition to abiraterone itself, part of the activity of the drug has been found to be due to a more potent active metabolite, δ4-abiraterone (D4A), which is formed from abiraterone by 3β-HSD. D4A is an inhibitor of CYP17A1, 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase, and 5α-reductase, and has also been found to act as a competitive antagonist of the AR reportedly comparable to the potent antagonist enzalutamide. However, the initial 5α-reduced metabolite of D4A, 3-keto-5α-abiraterone, is an agonist of the AR, and promotes prostate cancer progression. Its formation can be blocked by the coadministration of dutasteride, a potent and selective 5α-reductase inhibitor. Estrogenic activity There has been interest in the use of<unk>  for the treatment of breast cancer due to its ability to lower estrogen levels. However, abiraterone has been found to act as a direct agonist of the estrogen receptor, and induces proliferation of human breast cancer cells in vitro. If<unk>  is used in the treatment of breast cancer, it should be combined with an estrogen receptor antagonist like fulvestrant. In spite of its antiandrogenic and estrogenic properties,<unk>  does not appear to produce gynecomastia as a side effect. Other activities Due to inhibition of glucocorticoid biosynthesis,<unk>  can cause glucocorticoid deficiency, mineralocorticoid excess, and associated adverse effects. This is why the medication is combined with prednisone, a corticosteroid, which serves as a means of glucocorticoid replacement and prevents mineralocorticoid excess.<unk> , along with galeterone, has been identified as an inhibitor of sulfotransferases (SULT2A1, SULT2B1b, SULT1E1), which are involved in the sulfation of DHEA and other endogenous steroids and compounds, with Ki values in the sub-micromolar range. Pharmacokinetics After oral administration,<unk> , the prodrug form in the commercial preparation, is converted into the active form, abiraterone. This conversion is likely to be esterase-mediated and not CYP-mediated. Administration with food increases absorption of the drug and thus has the potential to result in increased and highly variable exposures; the drug should be consumed on an empty stomach at least one hour before or two hours after food. The drug is highly protein bound (>99%), and is metabolised in the liver by CYP3A4 and SULT2A1 to inactive metabolites. The drug is excreted in feces (~88%) and urine (~5%), and has a terminal half-life of 12 ± 5 hours.
Abiraterone acetate
Bisoctrizole
Osaterone acetate
Δ4-Abiraterone
Letrozole
Ingenol mebutate
Nandrolone decanoate
Nandrolone propionate