Moricizine, an Antiarrhythmic Agent, as a Potent Inhibitor of Hepatic Microsomal CYP1A

Abstract

We examined the inhibitory effect of moricizine (MOR) on hepatic cytochrome P-450 (CYP) in mice. Spectrophotometric analysis revealed that MOR had a relatively high affinity for CYP molecules. MOR most potently inhibited the CYP1A1-dependent ethoxyresorufin O-deethylation and the CYP1A2-dependent methoxyresorufin O-demethylation, among the metabolic reactions mediated by CYP1A, CYP2A, CYP2B, CYP2C, CYP2D, CYP2E, and CYP3A subfamilies expressed in untreated and CYP-inducer-treated hepatic microsomes. The inhibition constants (K_i) for ethoxyresorufin and methoxyresorufin O-dealkylations were 0.43 and 0.98 µmol/l, respectively. These K_i values were one to three orders of magnitude lower than those of cimetidine (CIM) and mexiletine (MEX) that have been accepted as the clinical inhibitors of CYP1A2 and were below the therapeutic serum concentration of MOR. Theophylline 3-demethylation and 8-hydroxylation in untreated hepatic microsomes, clinical probes for CYP1A2 activities, were subjected to marked and competitive inhibition by MOR with K_i values similar to that of methoxyresorufin O-demethylation, and the inhibitory potency of MOR was much higher than those of CIM and MEX. In addition, the zoxazolamine paralysis time, an in vivo measure of the hepatic CYP1A2 capacity, was markedly prolonged by pretreatment of mice with MOR rather than CIM and MEX, while the prolonging effect of MOR on the pentobarbital sleeping time, an indicator of the metabolic function of phenobarbital-inducible CYP species, was not so pronounced as compared with the zoxazolamine paralysis time. These results indicate that MOR acts as a potent and preferential inhibitor of hepatic CYP1A enzymes in vitro and in vivo.

Effect of Some Biologically Interesting Substituted Tetrahydro-1,4- Oxazines on Drug Metabolising Enzymes and on Inflammation

“…In this preliminary examination, we found it to be a CYP450 inducer with typical effects such as increase in liver weight, microsomal protein, total CYP450 and aminopyrine N-demethylation (a CYP3A activity) [22]. We also found a decrease in the action of zoxazolamine, an in vivo measure of the hepatic CYP1A2 capacity [23], and of hexobarbital. The observed reduction of body weight could be due to the sympathomimetic activity of (1) [1,2].…”