Temporary decrease in tacrolimus clearance in cytochrome P450 3A5 non-expressors early after living donor kidney transplantation: Effect of interleukin 6-induced suppression of the cytochrome P450 3A gene.

Abstract

Tacrolimus is important for immunosuppression in kidney transplantation. In this historical cohort and in vitro study, we evaluated the changes in tacrolimus pharmacokinetics early after living donor kidney transplantation and the effects of interleukin (IL)-6 on cytochrome P450 3A4 (CYP3A4) and cytochrome P450 3A5 (CYP3A5) expression. In the historical cohort study, 22 patients who met the inclusion criteria were classified into CYP3A5 expressors and non-expressors (n=16 and 6, respectively). The blood tacrolimus concentration per dose ratio (C/D) temporarily increased post-kidney transplantation on days 3-4 only in CYP3A5 non-expressors. The effects of IL-6 on CYP3A4 and CYP3A5 expression were also investigated in vitro using HepG2 and Caco-2 cells. IL-6 induced a significant concentration- and time-dependent decrease in CYP3A4 and CYP3A5 expression in both cells. The mean CYP3A4 expression level at 12hours after IL-6 exposure (% of 0hour) was 44.0 and 62.6 in HepG2 and Caco-2 cells, respectively, whereas the CYP3A5 expression level was 30.7 and 52.4, respectively. We hypothesize that CYP3A5 non-expressors might exhibit a temporary decrease in the oral clearance of tacrolimus via an increase in serum IL-6 concentrations early after kidney transplantation. These results may help develop strategies to improve kidney transplant outcome.