Science Links Japan | Oxidative Metabolism of Tacrolimus and its Metabolite by Human Cytochrome P450 3A Subfamily. TOP J-EAST List of Journal Titles (X) Xenobiotic Metabolism and Disposition(1999) Oxidative Metabolism of Tacrolimus and its Metabolite by Human Cytochrome P450 3A Subfamily. SHIRAGA T(Fujisawa Pharmaceutical Co., Ltd., Osaka) NIWA T(Fujisawa Pharmaceutical Co., Ltd., Osaka) TERAMURA Y(Fujisawa Pharmaceutical Co., Ltd., Osaka) KAGAYAMA A(Fujisawa Pharmaceutical Co., Ltd., Osaka) TSUTSUI M(Amersham K.k., Chiba) OHNO Y(National Inst. Hygienic Sci., Tokyo) IWASAKI K(Fujisawa Pharmaceutical Co., Ltd., Osaka) The cytochromes P450(CYPs) responsible for the oxidative metabolism of tacrolimus and its in vitro major metabolite M-I, the 13-O-mono-demethylated metabolite, were characterized in human liver microsomes. Human liver microsomes and ten human CYPs expressed in Hep G2 cells were used in the experiments. 1. When 14C-labeled tacrolimus(14C-tacrolimus) was incubated with human liver microsomes, M-I formation was mainly observed in the early stage of incubation, while many peaks of the more polar metabolites, including M-VII, the 13,15-O-di-demethylated metabolite, were detected in the late stage of incubation. When the microsomes were incubated with 14C-M-I, formation of M-VII and unidentified metabolites were observed. The rates of formation of M-I from 14C-tacrolimus in 10 different human liver microsomes correlated well with the activities of testosterone 6.BETA.-hydroxylation and tolbutamide methyl-hydroxylation, but not with the marker enzyme activities of other CYPs. The metabolism of both tacrolimus and M-I by human liver microsomes were inhibited by ketoconazole and anti-CYP3A4 antiserum. 2. After incubation of 14C-tacrolimus with Hep G2 cell lysates containing expressed human CYPs, M-I formation was observed in the reaction system with CYP3A3, 3A4 and 3A5, but not with CYP1A2,2A6,2B6,2C8,2C9,2D6 or 2E1.