Related Experiment Videos
Enzyme induction by moricizine: time course and extent in healthy subjects
I H Benedek1, A F Davidson, H J Pieniaszek
1Clinical Pharmacology Group, Du Pont Merck Pharmaceutical Company, Stine-Haskell Research Center, Newark, Delaware 19714.
Abstract:
Moricizine.HCl, a novel phenothiazine derivative with oral antiarrhythmic activity, was examined for its potential to induce its own hepatic metabolism and to alter the pharmacokinetics of the test substrate, antipyrine, in 12 healthy male subjects. Antipyrine oral clearance increased from a starting value of .74 mL/minute/kg to .98 (+32%, P < .01) after 7 days of moricizine administration (250 mg every 8 hours) and to 1.15 mL/minute/kg after 14 days (+47%, P < .05); t1/2 was correspondingly reduced. Moricizine oral clearance increased from a baseline of 3.01 L/hour/kg to 3.62 (+20%, P < .05) after 6 days of oral moricizine and 4.66 (+51%, not significant) after 13 days. Moricizine t1/2 was marginally, but consistently, increased (+23%, P < .05) instead of decreased as one would expect because of enzyme induction, presumably due to a decrease in systemic bioavailability and its influence on the oral volume of distribution. In half of the subjects who discontinued moricizine after 7 days, antipyrine pharmacokinetic values returned to near baseline 7 days later. Although moricizine was able to induce its own hepatic metabolism and that of antipyrine after 6 or 7 days of continuous administration, the electrocardiographic properties of moricizine did not appear to be altered by continuous dosing.
Insights
Moricizine hydrochloride, an oral antiarrhythmic, was found to induce its own hepatic metabolism and that of antipyrine in healthy subjects. This drug interaction did not affect moricizine's electrocardiographic properties.
Area of Science:
- Pharmacology
- Drug Metabolism
- Clinical Pharmacology
Background:
- Moricizine hydrochloride is a phenothiazine derivative used for its oral antiarrhythmic effects.
- Understanding drug-metabolizing enzyme induction is crucial for managing drug interactions and therapeutic efficacy.
Purpose of the Study:
- To investigate the potential of moricizine hydrochloride to induce its own hepatic metabolism.
- To assess the impact of moricizine hydrochloride on the pharmacokinetics of antipyrine, a model drug-metabolizing substrate.
Main Methods:
- 12 healthy male subjects received oral moricizine hydrochloride (250 mg every 8 hours).
- Pharmacokinetic parameters of antipyrine and moricizine were measured at baseline and during moricizine administration.
- Antipyrine oral clearance and half-life (t1/2) were analyzed.
Main Results:
- Antipyrine oral clearance significantly increased by 32% after 7 days and 47% after 14 days of moricizine administration.
- Moricizine oral clearance increased by 20% after 6 days and 51% after 13 days.
- Moricizine's half-life showed a marginal increase, potentially due to altered bioavailability.
Conclusions:
- Moricizine hydrochloride effectively induces its own hepatic metabolism and that of antipyrine after 6-7 days of continuous administration.
- Despite enzyme induction, the antiarrhythmic electrocardiographic properties of moricizine were not altered by continuous dosing.