The metabolism and excretion of loratadine (LOR), a long-acting non-sedating antihistamine, have been evaluated in male and female mice, rats and monkeys. Following a single (8 mg kg-1) oral administration of [14C]LOR, radioactivity was predominantly eliminated in the faeces. Profiling and characterization of metabolites in plasma, bile, urine and faeces from male and female mice, rats and monkeys showed LOR to be extensively metabolized with quantitative species and gender differences in the observed metabolites. In all species investigated, the primary biotransformation of LOR involved decarboethoxylation to form desloratadine (DL), subsequent oxidation (hydroxylation and N-oxidation) and glucuronidation. More than 50 metabolites were profiled using liquid chromatography-mass spectrometry (LC-MS) with in-line flow scintillation analysis (FSA) and characterized using LC-MSn techniques. The major circulating metabolite in male rats is a DL derivative in which the piperidine ring was aromatized and oxidized to pyridine-N-oxide. Much lower levels of the pyridine-N-oxide metabolite were observed in female rat plasma. In contrast, the relative amount of DL was notably higher in female than in male rats. The major circulating metabolite in either gender of mouse and male monkey is a glucuronide conjugate of an aliphatic hydroxylated LOR; in the female monkey, the major circulating metabolite is formed through oxidation of the pyridine moiety and subsequent glucuronidation. Qualitatively similar metabolic profiles were observed in the mouse, rat and monkey urine and bile, and the metabolites characterized resulted from biotransformation of LOR to DL, hydroxylation of DL and subsequent glucuronide conjugation. 5-Hydroxy-desloratadine was the major faecal metabolite across all three species irrespective of gender.