Climbazole is a new potent inducer of rat hepatic cytochrome P450.
We examined the effect of climbazole on the induction of rat hepatic microsomal cytochrome P450 (P450), and compared the induction potency with other N-substituted azole drugs such as clorimazole. We found that climbazole is found to be a potent inducer of rat hepatic microsomal P450 as clorimazole. Induced level of P450 by climbazole was almost similar in extent to clorimazole when compared with other imidazole drugs in a dose- and time-dependent manner. Parallel to the increase in P450, climbazole increased aminopyrine and erythromycin N-demethylase, ethoxycoumarin O-deethylase, and androstenedione 16 beta- and 15 alpha/6 beta hydroxylase activities; however, clorimazole did not induce aminopyrine N-demethylase activity irrespective of its marked increase in P450 content. Immunoblot analyses revealed that climbazole induced CYP2B1, 3A2 and 4A1. The present findings indicate that climbazole is a new potent inducer of hepatic microsomal P450 and drug-metabolizing enzymes like clorimazole, but it may have some differential mechanism(s) for these enzymes' induction in rat liver.
Kobayashi
Y
Y
Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
Suzuki
M
M
Ohshiro
N
N
Sunagawa
T
T
Sasaki
T
T
Tokuyama
S
S
Yamamoto
T
T
Yoshida
T
T
D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar
D000935:Antifungal Agents; D007093:Imidazoles; D003577:Cytochrome P-450 Enzyme System; C108286:climbazole; D010089:Oxidoreductases, N-Demethylating