Metabolism and transporter based drug–drug interaction of tacrolimus with nine co-medicated injections

•CYP3A4/5 is metabolism enzyme of tacrolimus by using human liver microsomes.•Tacrolimus was not the substrates of solute carrier (SLC) transporters.•Metabolism-based DDI induce high individual variability of tacrolimus exposure. Tacrolimus, also named FK506, is a well-known potent immunosuppressant agent, which is usually co-medicated with multiple drugs in solid organ transplant. The objective of this study was to evaluate DDI between tacrolimus and nine injections co-administered in patients receiving liver organ transplant. In this study, the cytochrome P450 enzymes (CYPs) inhibition assay were conducted by using pooled human liver microsomes, for supporting the evaluation of metabolism-mediated DDI. The transport substrate assay used to determine the transporter-mediated DDI, was conducted in the transfected HEK293 cell line expressing specific human transport proteins. All the tested drugs, especially alprostadil, methylprednisolone, and pantoprazole showed apparent inhibition on CYP3A4/5 with the half-maximal inhibitory concentration (IC50) from >0.5 μg/mL to 89.6 μg/mL, which also inhibited metabolism of tacrolimus in human liver microsomes, whose half time (T1/2) was prolonged from 5.04 to 35.3 min. However, tacrolimus was not the substrates of solute carrier (SLC) transporters including OATP1B1, OATP1B3, OAT1, OAT3, and OCT2, which indicated that the risk of transport-mediated DDI between tacrolimus and these nine drugs was likely to be low. These findings indicate that the metabolism-based DDI between tacrolimus and co-administered nine drugs seems to be the major cause of the high individual variability of tacrolimus exposure in patients with solid organ transplant and should be further studied.