ABSTRACT
[14C]-Penticainide, 2-[2-(diisopropylamino) ethyl]-4-methyl-2-(2-pyridyl)pentanamide, a new antiarrhythmic agent, was administered as a single oral dose to rats, dogs, baboons (30 mg kg-1) and to healthy, informed volunteers (300 mg). Excretion of radioactivity was followed for 3 days in urine and faeces. In man, about 95% of the administered radioactivity was eliminated in the urine and levels ranging from 56 to 86% were observed in animals. The radioactivity that did not appear in the urine was almost quantitatively recovered in the faeces. Metabolites in urine were isolated by thin-layer chromatography and identified by mass spectrometry and nuclear magnetic resonance. In addition to the unchanged drug, nine metabolites and an artifact compound resulting from the partial degradation of one metabolite, were identified among the thirteen radioactive compounds detected. The major metabolites resulted from N-dealkylation of the diisopropyl moiety, oxidation of the isobutyl side-chain and hydrolytic cleavage of the amide. Comparison of the excretion and metabolic patterns of animals with those of man revealed that the dog should be a most suitable model for predicting the pharmacological and toxicological effects of penticainide in man.
Subject(s)
Propylamines/urine , Pyridines , Animals , Carbon Radioisotopes , Chromatography, Thin Layer/methods , Dogs , Feces/analysis , Gas Chromatography-Mass Spectrometry/methods , Humans , Kinetics , Magnetic Resonance Spectroscopy/methods , Papio , Propylamines/metabolism , Rats , Species SpecificityABSTRACT
Two selective and sensitive methods for the quantitative analysis of butofilol in human plasma and urine are discussed. The first method is a gas chromatographic assay with electron-capture detection using extraction with toluene, several clean-up procedures and derivatization. The second method is based on high-performance liquid chromatography and a single extraction with dichloromethane. The two assay methods were applied to the determination of the same human plasma samples after administration of a single, oral 200-mg dose of butofilolol. A good correlation between the results (inter-laboratory comparison) is obtained, validating both techniques.
