AbstractThe excretion and biotransformation of astemizole (AST) were studied after single administration in rats (0.16 or 10 mg/kg), guinea‐pigs (0.16 mg/kg), dogs (1 or 10 mg/kg) and humans (30 mg), using three different radiolabels. Orally administered AST was well absorbed and almost completely metabolized in rats, dogs, and humans, whereas in guinea‐pigs about 17% of dose was excreted as parent AST. In the four species urinary excretion of the radioactivity (5–15%) was much less than their fecal excretion (60–90%). Excretion rate of the radioactivity decreased in the order rat ≥ guinea‐pig ≥ dog ≥ man. In male rats, biliary excretion amounted to 70% at 24 hr after dosing, whereas about 45% of the biliary radioactivity was subjected to enterohepatic circulation. The major metabolites were characterized by high performance liquid chromatography (HPLC) and mass spectrometry. A mass balance of the metabolites was made up by HPLC with on‐line radioactivity detection. The major metabolic pathways of AST in the four species were oxidative O‐demethylation, aromatic hydroxylation at the benzimidazole moiety, and oxidative N‐dealkylation at the piperidine nitrogen. Phenolic metabolites resulting from the two former pathways were excreted as their glucuronides in the bile. Desmethylastemizole (DES‐AST) was the main metabolite in rats, 6‐hydroxy‐desmethylastemizole (6‐OH‐DES‐AST) the main metabolite in dogs. In humans, about equal relative amounts of DES‐AST, 6‐OH‐DES‐AST, and norastemizole were found. Sex differences in rats were only minor. The mass balance of the metabolites after a 6‐week dosing at 1 mg/kg/day in dogs was very similar to that after a single dose.