In order to better understand the pharmacokinetic differences between acute and chronic regimens of the basic lipophilic antiarrhythmic, amiodarone (AM), a mass-balanced single-dose study ([14C]AM, 50 mg/kg, i.v.) was carried out until total elimination had been achieved (10 days). Total drug, AM and desethylamiodarone (DEA) were determined in plasma, eight tissues and excreta of rats with constant body weight. Three exponential terms were sufficient to describe the plasma concentration-time curve of unchanged AM with a long terminal half-life of 131 hr. An equally long terminal half-life of AM could also be observed in all tissues investigated. After 5 min, 42% of the radioactivity appeared in the liver, where it underwent redistribution to muscle, skin and, ultimately, adipose tissues. Whereas plasma and liver contained mainly unidentified metabolites and little DEA, unchanged AM predominated in all other tissues. According to the time-integrated parameters of distribution, AM has a potential to accumulate in adipose tissue under chronic administration. In contrast, DEA accumulation would be likely to occur in lean tissues, mainly in the lung. In 10 days, 94% of the injected radioactivity was excreted in feces and less than 2% in urine. Almost all of the excreted radioactivity consisted of unidentified metabolites, indicating that both AM and DEA are eliminated by metabolism.