Meropenen inhibits the cytochrome P450 (CYP) 3A-dependent biotransformation of the immunosuppressive tacrolimus in human liver microsomes

Abstract

Tacrolimus (TAC), a immunosuppressive drug used in solid organ transplantation, is metabolized by CYP3A4 and 3A5. The simultaneous administration of TAC and meropenem (MEP) in pediatric kidney transplant patients may led to a significant increase in plasma concentrations of TAC. We hypothesized that this negative pharmacokinetic interaction is due to the inhibition of the CYP3A4-mediated biotransformation of TAC by MEP, particularly in those individuals lacking the expression of CYP3A5. The aim of this study was to evaluate in vitro the potential metabolic interaction between TAC and MEP. Human liver microsomes were prepared with discard liver samples obtained from healthy donors (n=2) and individuals subjected to tumor resection (n=2). The specific CYP3A-dependent enzyme activity, testosterone 6-beta hydroxylase, was assayed in the absence (control) and in presence of TAC (5 and 20 µM), MEP (10 µM) and the combinations of TAC and MEP. TAC, incubated at 5 and 20 µM, inhibited (p<0.05) the CYP3A-mediated 6-beta hydroxylation of testosterone (18±13% and 51±16%, respectively). This finding may confirm the high affinity of CYP3A4 for TAC. MEP, at 10 µM, did not affect this enzyme reaction. After co-incubations of TAC and MEP, testosterone 6-beta hydroxylase activities resembled those observed when TAC was incubated alone. In control assays, rates of TAC metabolism were 30±20 and 120±40 pmol/min.mg of microsomal protein, respectively. MEP, at 10 µM, significantly inhibited (p<0.05) the hepatic biotransformation of TAC; rates (pmol/min.mg) of TAC metabolism (at 5 and 20 µM) were 20±10 (43±24% inhibition) and 70±50 (49±23% inhibition), respectively. These preliminary results show a metabolic interaction between TAC and MRP on CYP3A-dependent metabolism in human liver. The enhancement of the systemic availability of TAC observed in vivo in the co-administration with MEP would be due to the inhibition of the CYP3A4-dependent biotransformation of the immunosuppressive drug.