Enzyme-inducing effects of bicalutamide in mouse, rat and dog.
1. Bicalutamide, a non-steroidal antiandrogen, produced dose-related increases in total cytochrome P450 (P450) and aldrin epoxidase, but had no effect on ethoxyresorufin O-deethylase, when administered for 10 weeks at 0, 25, 75 and 150 mg/kg/day to the male dog. 2. In the male and female mouse, bicalutamide, administered orally at 75 mg/kg/day for 3 months, produced marked induction of total P450, ethoxycoumarin O-deethylase, pentoxyresorufin O-dealkylase and aldrin epoxidase. Immunoblotting showed that bicalutamide produced substantial induction of CYP2B isoforms, with lower increases in CYP3A. Immunohistochemistry of mouse liver sections also showed marked increases in the level of CYP2B isoforms, with an increase in the extent of distribution from centrilobular to panlobular; CYP3A isoforms were also increased, but to a lesser degree. 3. Bicalutamide, administered as 14 daily oral doses (250 mg/kg) to groups of male rats, produced increases primarily in ethoxycoumarin O-deethylase and erythromycin N-demethylase, together with smaller increases in ethoxyresorufin O-deethylase and pentoxyresorufin O-dealkylase; these changes were reversible within 7 days. Immunoblotting of microsomes and immunocytochemistry of liver sections showed that bicalutamide markedly induced CYP3A1, but had little effect on CYP2B1 in rat. Compared with dexamethasone, bicalutamide is a more selective inducer of CYP3A1 in rat. 4. Bicalutamide, administered to rats as 14 daily oral doses of 10 mg/kg, induced its own metabolism by stimulating both aromatic hydroxylation and direct glucuronidation. This effect was apparently offset by a concomitant decrease in hydrolysis of bicalutamide, resulting in no marked change in total amounts of dose eliminated over 2 days. 5. Although the secondary effects of enzyme induction result in thyroid hypertrophy and adenoma in rat and hepatocellular carcinoma in mouse following chronic administration of bicalutamide, these changes are considered to have little clinical relevance. In any case, bicalutamide does not produce enzyme induction in man at clinically relevant dose levels.
McKillop
D
D
Safety of Medicines Department, Zeneca Pharmaceuticals, Macclesfield, UK.
Butters
C J
CJ
Hill
S J
SJ
Simons
P J
PJ
Edwards
T L
TL
Doughty
S E
SE
D015660:7-Alkoxycoumarin O-Dealkylase / Q000096:biosynthesis*; D000284:Administration, Oral; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000813:Anilides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001646:Bile / Q000378:metabolism; D002478:Cells, Cultured; D019362:Cytochrome P-450 CYP2B1 / Q000096:biosynthesis*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004285:Dogs; D004790:Enzyme Induction; D005243:Feces / Q000737:chemistry; D005260:Female; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D009251:NADPH-Ferrihemoprotein Reductase / Q000096:biosynthesis; D009570:Nitriles; D051381:Rats; D011919:Rats, Inbred Strains; D014105:Tosyl Compounds
D000726:Androgen Antagonists; D000813:Anilides; D009570:Nitriles; D014105:Tosyl Compounds; D003577:Cytochrome P-450 Enzyme System; C053541:bicalutamide; D006899:Mixed Function Oxygenases; C019647:aldrin epoxidase; D015660:7-Alkoxycoumarin O-Dealkylase; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D019362:Cytochrome P-450 CYP2B1; D051544:Cytochrome P-450 CYP3A; D009251:NADPH-Ferrihemoprotein Reductase