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

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.