Bicalutamide: Mechanism of Action, Metabolism, and Safety
Aug 29,2025
Introduction
Bicalutamide is a nonsteroidal pure antiandrogen given at a dosage of 150mg once daily as monotherapy for the treatment of early (localised or locally advanced) nonmetastatic prostate cancer. It is used at a dosage of 50mg once daily in combination with a luteinising hormone-releasing hormone analogue or surgical castration for the treatment of advanced prostate cancer. [1]
Mechanism of Action of Bicalutamide
Bicalutamide is a pure antiandrogen that binds to rat, dog, and human prostate; the affinity compared with the natural ligand 5α-dihydrotestosterone is low, but bicalutamide has an affinity for the rat androgen receptor approximately four times higher than hydroxyflutamide, the active metabolite of flutamide. Bicalcutamide also binds to androgen receptors found in the LNCaP human prostate tumor and the Shionogi S115 mouse mammary tumor cell line, as well as androgen receptors transfected into CV-1 and HeLa cells. In all cases, bicalutamide behaves as a pure antiandrogen and inhibits gene expression and cell growthstimulated by androgen. Studies with the LNCap cell line are particularly interesting, as these cells contain a mutated androgen receptor (codon 868, Thr→Ala), which behaves idiosyncratically with other antiandrogens (cyproterone acetate and flutamide); both these antiandrogens act as agonists in this cell line and stimulate proliferation. [2]
Metabolic mechanism of Bicalutamide
Bicalutamide is a racemate and its antiandrogenic activity resides almost exclusively in the (R)-enantiomer, with little, if any, activity in the (S)-enantiomer. (R)-Bicalutamide is slowly and saturably absorbed, but absorption is unaffected by food. It has a long plasma elimination half-life (1 week) and accumulates about 10-fold in plasma during daily administration. (S)-Bicalutamide is much more rapidly absorbed and cleared from plasma; steady-state concentrations (Css) of (R)-bicalutamide are 100-fold higher than those of (S)-bicalutamide. Css increases linearly with doses up to 50mg, but nonlinearly at higher doses, reaching a plateau above 300mg. Css is higher in Japanese than in Caucasians, but no relationship with degree of renal impairment, bodyweight or age exists. Although mild-to-moderate hepatic impairment does not affect pharmacokinetics, there is evidence for slower elimination of (R)-bicalutamide in subjects with severe hepatic impairment. [1]
Bicalutamide metabolites are excreted almost equally in urine and faeces with little or no unchanged drug excreted in urine; conversely, unchanged drug predominates in plasma. Bicalutamide in faeces is thought to arise from hydrolysis of bicalutamide glucuronide and from unabsorbed drug. Bicalutamide appears to be cleared almost exclusively by metabolism; this is largely mediated by cytochrome P450 (CYP) for (R)-bicalutamide, but glucuronidation is the predominant metabolic route for (S)-bicalutamide. (S)-Bicalutamide is metabolised in vitro by CYP3A4, and it is probable that this isoenzyme is also responsible for the metabolism of (R)-bicalutamide. In vitro data suggest that (R)-bicalutamide has the potential to inhibit CYP3A4 and, to a lesser extent, CYP2C9, 2C19 and 2D6. However, using midazolam as a specific CYP3A4 marker, no clinically relevant inhibition is observed in vivo with bicalutamide 150mg. Although bicalutamide is a CYP inducer in laboratory animals, dosages ≤150 mg/day have shown no evidence of enzyme induction in humans. [1]
Daily administration of bicalutamide increases circulating levels of gonadotrophins and sex hormones; although testosterone increases by up to 80%, concentrations in most patients remain within the normal range. Bicalutamide produces a dose-related decrease in prostate-specific antigen (PSA) at dosages ≤150 mg/day. However, little relationship is observed between median PSA reduction and (R)-bicalutamide Css. [1]
Safety of Bicalutamide
Bicalutamide is a new antiandrogen that offers the convenience of once-daily administration, demonstrated activity in prostate cancer, and an excellent safety profile. Because it is effective and offers better tolerability than flutamide, bicalutamide represents a valid first choice for antiandrogen therapy in combination with castration for the treatment of patients with advanced prostate cancer. [3]
References
[1] Cockshott, I.D. Bicalutamide. Clin Pharmacokinet 43, 855–878 (2004). https://doi.org/10.2165/00003088-200443130-00003
[2] Furr, B. J. A., & Tucker, H. (1996). The preclinical development of bicalutamide: pharmacodynamics and mechanism of action. Urology, 47(1), 13-25.
[3] Kolvenbag, G. J., & Blackledge, G. R. (1996). Worldwide activity and safety of bicalutamide: a summary review. Urology, 47(1), 70-79.
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