In-vitro metabolic studies of tacrolimus using precision-cut rat and human liver slices

The objective of this study was to investigate the in-vitro metabolism of tacrolimus in liver slices from rats and humans. [14C]Tacrolimus (2 or 20 microM) was incubated with precision-cut human and rat liver slices in 12-well plates for up to 12 h. Concentrations of tacrolimus and metabolites were determined by high-performance liquid chromatography (HPLC) radiochromatography. The 13-O-demethylated tacrolimus metabolite (M-I) was the major oxidative metabolite in both rat and human liver slices. The other primary metabolites of tacrolimus (M-II, M-III, and M-IV) were not seen in either species. Unidentified peaks, which eluted early in the HPLC system, were probably due to secondary or conjugated metabolites. The eluate had no pharmacological activity. The finding that M-I was the major tacrolimus metabolite in both human and rat liver slice preparations is consistent with previous studies of rat and human liver microsomes.