Pharmacokinetic Interactions of Moricizine and Diltiazem in Healthy Volunteers

Abstract

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.

In Vitro and in Vivo Drug Interactions Involving Human Cyp3a

“…These levels are several orders of magnitude lower than the reported K i value of 50-75 µM (Table 1). Nevertheless, the oral clearance of several CYP3A substrates, including cyclosporine (112), midazolam (131), triazolam (132), morizicine (133), and quinidine (134) were found to be markedly (>75%) reduced when diltiazem was co-administered compared to the drug substrate alone. Additionally, diltiazem inhibited the CYP3A-mediated metabolism, of carbamazepine (135) and theophylline (136), which have low intrinsic clearances that preclude the likelihood of the discrepancy resulting from selective intestinal CYP3A inhibition.…”

Moricizine Bioavailability via Simultaneous, Dual, Stable Isotope Administration: Bioequivalence Implications

“…This is possibly due to the gastrointestinal presystemic component of the first-pass effect, given that moricizine may be a CYP 3A4 substrate. 12 Despite the moricizine tablet's 75% in 30 minutes dissolution specification, 5 the 5% to 10% increase in the ratio of mean bioequivalence metrics may be site specifically mediated given that 3A4 isozymes are most dense along the proximal gastrointestinal tract. 13 The use of stable isotopes to evaluate relative bioavailability in situations where saturable processes may affect the rate and extent of absorption of one labeled formulation because of the presentation of the other should be used with caution as the principle of superposition will likely not apply, and the interpretation of results may be biased.…”

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

“…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].…”