ENZYME-INDUCING EFFECTS OF BICALUTAMIDE IN MOUSE, RAT AND DOG

1. Bicalutamide, a non-steroidal antiandrogen, produced dose-related i ncreases in total cytochrome P450 (P450) and aldrin epoxidase, but had no effect on ethoxyresorufin O-deethylase, when administered for 10 w eeks at 0, 25, 75 and 150 mg/kg/day to the male dog. 2. In the male an d female mouse, bicalutamide, administered orally at 75 mg/kg/day for 3 months, produced marked induction of total P450, ethoxycoumarin O-de ethylase, pentoxyresorufin O-dealkylase and aldrin epoxidase. Immunobl otting showed that bicalutamide produced substantial induction of CYP2 B isoforms, with lower increases in CYP3A. Immunohistochemistry of mou se liver sections also showed marked increases in the level of CYP2B i soforms, with an increase in the extent of distribution from centrilob ular to panlobular; CYP3A isoforms were also increased, but to a lesse r degree. 3. Bicalutamide, administered as 14 daily oral doses (250 mg /kg) to groups of male rats, produced increases primarily in ethoxycou marin O-deethylase and erythromycin N-demethylase, together with small er increases in ethoxyresorufin O-deethylase and pentoxyresorufin O-de alkylase; these changes were reversible within 7 days. Immunoblotting of microsomes and immunocytochemistry of liver sections showed that bi calutamide markedly induced CYP3A1, but had little effect on CYP2B1 in rat. Compared with dexamethasone, bicalutamide is a more selective in ducer of CYP3A1 in rat. 4. Bicalutamide, administered to rats as 14 da ily oral doses of 10 mg/kg, induced its own metabolism by stimulating both aromatic hydroxylation and direct glucuronidation. This effect wa s apparently offset by a concomitant decrease in hydrolysis of bicalut amide, resulting in no marked change in total amounts of dose eliminat ed over 2 days. 5. Although the secondary effects of enzyme induction result in thyroid hypertrophy and adenoma in rat and hepatocellular ca rcinoma in mouse following chronic administration of bicalutamide, the se changes are considered to have little clinical relevance. In any ca se, bicalutamide does not produce enzyme induction in man at clinicall y relevant dose levels.