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. [C-14]Tacrolimus (2 or 20 mu M) was incubated with precision-cut human and rat liver sl ices in 12-well plates for up to 12 h. Concentrations of tacrolimus an d metabolites were determined by high-performance liquid chromatograph y (HPLC) radiochromatography. The 13-O-demethylated tacrolimus metabol ite (M-I) was the major oxidative metabolite in both rat and human liv er slices. The other primary metabolites of tacrolimus (M-II, M-III, a nd M-IV) were not seen in either species. Unidentified peaks, which el uted early in the HPLC system, were probably due to secondary or conju gated metabolites. The eluate had no pharmacological activity. The fin ding that M-I was the major tacrolimus metabolite in both human and ra t liver slice preparations is consistent with previous studies of rat and human liver microsomes.