Androcur Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: Androcur is an antiandrogenic hormone preparation.
Cyproterone acetate inhibits competitively the effect of androgens at androgen-dependent target organs, e.g. it shields the prostate from the effect of androgens originating from the gonads and/or the adrenal cortex. Prostatic carcinoma and its metastases are in general androgen-dependent, Androcur therefore exerts a direct antiandrogenic action on the tumour and its metastases.
Cyproterone acetate in addition has a progestogenic action exerting a negative feedback effect centrally on the hypothalamic receptors, so leading to a reduction in gonadotropin release, and hence to diminished production of testicular androgens. Treatment with cyproterone acetate in men results in a reduction of sexual drive and potency and inhibition of gonadal function. These changes are reversible following discontinuation of the therapy.
The antigonadotropic effect of cyproterone acetate is also exerted when the substance is combined with LHRH agonists. The initial increase of testosterone provoked by this substance group is decreased by cyproterone acetate.
In women, hirsutism is diminished, but also androgen-dependent loss of scalp hair and elevated sebaceous gland function are reduced. During the treatment ovarian function is inhibited.
Prolactin levels can increase slightly under higher doses of cyproterone acetate. Studies showed increased prolactin levels up to 20ng/mL (normal range 5-15ng/mL). There are no data for periods longer than 6 months.
Clinical trials: No data available.
Pharmacokinetics: Absorption: Following oral administration, cyproterone acetate is completely absorbed over a wide dose range.
The ingestion of 50 mg of cyproterone acetate gives maximum serum levels of about 140 ng/mL at about 3 hours. Thereafter, drug serum levels declined during a time interval of typically 24 to 120 hours, with a terminal half-life of 43.9±12.8h. The total clearance of cyproterone acetate from serum was determined to be 3.5±1.5 mL/min/kg. The absolute bioavailability of cyproterone acetate is unknown. Relative bioavailability was calculated, in a study of eight young women, from a dose-corrected comparison of area under the curves of serum levels after 100 mg oral and 300 mg intramuscular depot administration and was found to be 80±30 % when averaged over all volunteers (range 23%-119 %).
Distribution: The major part of circulating cyproterone acetate is bound to serum albumin. In a study in 15 women receiving 2 mg cyproterone acetate in combination with 35 μg ethinyloestradiol, the free fraction of cyproterone acetate was about 3.5-4 %. Because protein binding is non-specific, changes in SHBG (sex hormone binding globulin) levels do not affect the pharmacokinetics of cyproterone acetate.
Metabolism: Cyproterone acetate is metabolised by various pathways, including hydroxylations and conjugations. The main metabolite in human plasma is the 15β-hydroxy derivative. Some dose parts are excreted unchanged with bile fluid. Phase 1 metabolism of cyproterone acetate is mainly catalysed by the cytochrome P450 enzyme CYP3A4.
Excretion: In a study in 6 women administered a ¹⁴C labelled dose of 2 mg cyproterone acetate in combination with 50 μg oestrogen, approximately 30 % of the label was found in the urine and 58 % in the faeces. The renal and biliary excretion was determined to proceed with a half-life of 1.9 days. Metabolites from plasma were eliminated at a similar rate (half-life of 1.7 days).
Steady state conditions: According to the long half-life of the terminal disposition phase from plasma (serum) and the daily intake, an accumulation of cyproterone acetate by a factor of about 3 can be expected in the serum during repeated daily administration.
Toxicology: Preclinical safety data: Genotoxicity: Cyproterone acetate was negative in a standard battery of genotoxicity studies. However, further tests showed that cyproterone acetate was capable of producing hepatocyte DNA adducts in rats, dogs and monkeys (and an increase in DNA-repair activity in rats) in vivo and also in freshly isolated rat and human liver cells in vitro. This DNA-adduct formation occurred at exposures that might be expected to occur in the recommended dose regimens for Androcur. In vivo consequences of cyproterone acetate treatment were the increased incidence of focal, possibly pre-neoplastic, liver lesions in which cellular enzymes were altered in female rats, and an increase of mutation frequency in transgenic rats carrying a bacterial gene as target for mutation. The clinical relevance of these findings presently remains uncertain.
Carcinogenicity: Long-term animal carcinogenicity studies were performed in rats and mice. In one rat study, an increased incidence of hepatomas was reported at oral dose levels of 50 mg/kg cyproterone acetate and above. In mouse (and a second rat) carcinogenicity studies, increases in benign proliferative changes (nodular hyperplasia) in liver cells of female mice and male and female rats were reported at oral doses of 2 mg/kg. Because of shortcomings in these studies (inadequate pharmacokinetic data and the need to reassess the liver pathology), the carcinogenic potential of cyproterone acetate in animals could not be determined.
Clinical experience and limited epidemiological data available to date do not appear to have supported an increased incidence of hepatic tumours in humans. However, it must be borne in mind that steroidal sex hormones can promote the growth of certain hormone-dependent tissues and tumours.