Subchronic oral and intravenous (i.v.) safety evaluation and pharmacokinetics in rats and dogs of ipazilide fumarate (Win 54, 177-4), an antiarrhythmic agent.

Ipazilide fumarate (Win 54, 177-4) is a chemically novel antiarrhythmic agent that prolongs ventricular refractoriness and possesses antiectopic activity. Subchronic (29 days) nonclinical safety evaluation of ipazilide was conducted following oral and iv administration in Sprague-Dawley rats (20-320 mg/kg oral and 1.25-10 mg/kg iv) and 14 and 28 days in beagle dogs (3-30 mg/kg oral and 2.5-20 mg/kg iv). The pharmacokinetic parameters of ipazilide indicate that ipazilide is absorbed (tmax less than or equal to 1 hr) in fasted rats and dogs following single and repeated oral administrations. The apparent elimination half-life in the two species is approximately 1 hr (except in rats at a dosage of 320 mg/kg), suggesting rapid clearance. Increases in liver weights (rats 320 mg/kg) accompanied by the observation of centrilobular hypertrophy of hepatocytes were considered an expression of an adaptive metabolic response of the liver to ipazilide and may be associated with the induction of microsomal enzymes. Duodenal villous atrophy and epithelial hyperplasia (rats, 80 and 320 mg/kg) were interpreted to represent an irritant response to the drug. Local irritation was also observed at the injection site in rats and dogs. Dogs tolerated the oral and the iv administration of ipazilide at dosages of up to 30 and 20 mg/kg, respectively. Despite emesis (oral dogs), which was reduced in frequency following repeated treatment over several weeks, plasma levels in treated dogs (i.e., Cmax 4-5 micrograms/ml) were approximately twice that required to convert spontaneous arrhythmias in the conscious dog model 24 hr after myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)