Pharmacodynamics of abiraterone acetate. , showing the actions of 17α-hydroxylase and 17,20-lyase in green boxes at left.
Antiandrogenic activity Abiraterone, the
active metabolite of abiraterone acetate, 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 abiraterone acetate thus decreases circulating levels of androgens such as DHEA,
testosterone, and
dihydrotestosterone (DHT). Abiraterone acetate, 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). 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. Its formation can be blocked by the coadministration of
dutasteride, a potent and selective
5α-reductase inhibitor. 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.
Other activities Due to inhibition of
glucocorticoid biosynthesis, abiraterone acetate 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. Abiraterone acetate, 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, abiraterone acetate, 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 metabolized 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. ==Chemistry==