Enzyme Induction by Moricizine: Time Course and Extent in Healthy Subjects

Benedek, Irma H.; Davidson, Anna F.; Pieniaszek, Henry J.

doi:10.1002/j.1552-4604.1994.tb03982.x

Cited by 12 publications

(2 citation statements)

References 27 publications

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“…As the existence of a number of metabolites was confirmed in animals and humans [49,50], some metabolites may be involved in CYP1A inhibition in addition to MOR itself. However, the serum MOR concentration reaches 2MOR is susceptible to alterations in its pharmacokinetic behavior when given in combination with other drugs capable of inhibiting the hepatic CYP system [52], but there have been no reports describing that MOR conversely reduced the metabolic clearance of coadministered drugs, although MOR exerts CYP enzyme inducing effects [4][5][6][7][8]. In the present study, we provided the first evidence that MOR is a potent inhibitor of hepatic CYP1A enzymes.…”

Section: Discussionmentioning

confidence: 69%

“…This interpretation is based on the clinical findings that MOR moderately enhances not only its own metabolism [4], but also the oxidative metabolism of coadministered drugs, including antipyrine [5], theophylline [6], and diltiazem [7] following long-term administration. The inductive effect of MOR was also confirmed by an experiment using rats, showing that the relative liver weight and some CYPdependent hepatic enzyme activities were significantly increased by chronic MOR exposure [8].…”

Section: Introductionmentioning

confidence: 99%

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

Konishi

Morita²,

Minouchi³

et al. 2002

Pharmacology

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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.

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

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

Konishi

Morita²,

Minouchi³

et al. 2002

Pharmacology

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Pharmacokinetic Interactions of Moricizine and Diltiazem in Healthy Volunteers

Shum

Pieniaszek

Robinson

et al. 1996

The Journal of Clinical Pharma

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Sixteen healthy male volunteers completed a nonrandomized, sequential, three-phase study. The three phases were 1) moricizine at 250 mg every 8 hours for 7 days with 12 days washout; 2) diltiazem at 60 mg every 8 hours for 7 days; and 3) concomitant administration of moricizine at 250 mg and diltiazem at 60 mg every 8 hours for 7 days. The plasma concentration-time profiles were obtained at the end of each phase for moricizine, diltiazem (with its metabolites desacetyl-diltiazem and N-desmethyl-diltiazem), and both when administered together. Under steady-state conditions, there was a two-way (opposing) pharmacokinetic drug interaction when moricizine and diltiazem were coadministered in healthy volunteers. Both maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to the end of administration (AUC tau) of moricizine increased significantly by 88.9% and 121.1%, respectively. Oral clearance (Clo) decreased by 54%. The terminal half-life (t1/2) of moricizine was not affected, however (2.1 +/- 0.5 hours versus 2.4 +/- 0.7 hours). It is believed that these changes were due to the inhibition of hepatic metabolism by diltiazem, which resulted in an increased systemic availability of moricizine. Moricizine had opposite effects on the pharmacokinetics of diltiazem. Moricizine decreased the Cmax of diltiazem significantly (by 36%) and increased Clo by 52%. A small but statistically significant decrease in the t1/2 from 4.6 +/- 1.3 hours to 3.6 +/- 0.7 hours was observed. Despite this result, no remarkable changes (e.g., in Cmax, AUC, or t1/2) were found for the two major diltiazem metabolites desacetyl-diltiazem and N-desmethyl-diltiazem. It appears that the pharmacokinetic interaction of moricizine and diltiazem was metabolic. With the increase in moricizine concentrations and the decrease in diltiazem concentrations, adjustments in dose may be required to achieve optimal therapeutic response when coadministering both agents.

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Moracizine

2006

Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions

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Enzyme Induction by Moricizine: Time Course and Extent in Healthy Subjects

Cited by 12 publications

References 27 publications

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

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

Pharmacokinetic Interactions of Moricizine and Diltiazem in Healthy Volunteers

Moracizine

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