Metabolism of temelastine (SK&F 93944) in hepatocytes from rat, dog, cynomolgus monkey and man

A species comparison of the metabolic pathways of temelastine has been made using hepatocyte preparations from rat, dog, cynomolgus monkey, and man. Metabolites and unchanged temelastine were separated by HPLC and were compared with authentic standards by retention. The characteristic UV spectra of SK&F 93944 and its metabolites aided in the preliminary identification of metabolites in hepatocyte incubates, subsequently confirmed by liquid chromatography/mass spectrometry (LC/MS). The metabolic profile of temelastine is complex, both in vivo and in vitro, but all of the metabolites identified unambiguously from in vivo studies have also been demonstrated in vitro. Moreover, the time-dependent nature of the metabolic profile has been investigated in rat hepatocytes. Marked differences in the rate of production, extent of accumulation, and distribution between cells and culture medium have been observed for specific metabolites. Species differences in the metabolism of temelastine by rat, dog, cynomolgus monkey, and human hepatocytes have been observed. In particular, SK&F 94224 (a hydroxylated metabolite of temelastine) was not detected in human hepatocyte incubations at appreciable concentrations, but was present in varying amounts in the other species and especially in incubations from dog hepatocytes. Temelastine N-glucuronide was not detected in the rat hepatocyte system but was present to a modest or significant extent in hepatocyte incubations from dog, cynomolgus monkey, and man.