Climbazole is a new potent inducer of rat hepatic cytochrome P450.

Abstract

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 and 15 /6 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.

Induction and Inhibition of Cytochrome P450 and Drug-Metabolizing Enzymes by Climbazole.

“…No toxic manifestations were observed after treatment with climbazole even at higher dose levels (0.80 mmol/kg). As expected, 20) climbazole slightly increased the P450 content at the lower dose (0.10 mmol/ kg) and significantly induced P450 with increasing dose up to 0.80 mmol/kg in a dose-related manner in both LongEvans and Wistar rats (Fig. 1B).…”

“…1B). The results indicate that climbazole produces dose-dependent induction of P450 without strain differences between Wistar 20) and Long-Evans female rats. The effects of climbazole on drug-metabolizing enzyme activities are shown in Fig.…”

“…Erythromycin N-demethylase activity in Long-Evans rats was also examined (data not shown), although, we did not observe the induction of catalytic activity at any dose level. 20) These findings indicate that strain differences exist in the induction of drug-metabolizing enzyme activity by climbazole in the rat liver.…”

“…20) Based on our previous findings, 20) we first examined whether there are strain differences in the induction of P450 and drug-metabolizing enzyme activities by climbazole in Long-Evans rats because there is little information on the induction response of hepatic enzymes in this strain. No toxic manifestations were observed after treatment with climbazole even at higher dose levels (0.80 mmol/kg).…”

Pharmacokinetic Study of .BETA.-Methyldigoxin by Enzyme Immunoassay Using a Novel Specific Antiserum in Rats.

“…Then, so far, it has also been shown that several diseases such as hepatic and renal failures and administration of drugs such as corticosteroids resulted in producing strong abilities to increase endogenous Dx3-like compound levels and induce metabolic enzyme activity. [17][18][19][20][21] Rameis et al have suggested that demethylation at C-4ٞ of MDx3 was remarkably reduced in patients with cirrhosis. 17) Due to changes of hepatic and renal function and/or metabolic enzyme activity in the body, monitoring of MDx3 by EIA-II may not be successfully carried out after administration of MDx3.…”