Purpose: The present study was designed to determine the effect ratio of CYP3A5 on the metabolism of tacrolimus that is used as an immunosuppressant for tissue transplantation.Methods: To determine the role of CYP3A4 and CYP3A5 on tacrolimus metabolism, rats were divided into five groups as: group 1 control group, tacrolimus only 1 mg/kg i.v. , group 2 pretreated with ritonavir 5 mg/kg, i.v. 1 h before administration of tacrolimus , group 3 pretreated with indinavir 10 mg/kg, i.v. 1 hour before administration of tacrolimus , groups 4 and 5, in addition to the protocol of groups 2 and groups 3. Dexamethasone 100 mg/kg, p.o. was administered for 2 days before the experimental study to each group. To estimate the area under curve AUC of tacrolimus, the blood samples were collected after 15, 30, 60, 75, and 90 min and after 2, 3, 4, 8, and 24 h, and MEIA method was used to determine whole blood levels of tacrolimus.Results: Although the AUCs of tacrolimus in group 2 533.5±139.85 ng.h/mL and group 3 3428±683 ng.h/mL were higher than the control group 394±127 ng.h/mL , the only significant difference was found in ritonavir pretreated group group 3 . In dexamethasone pretreated groups, the AUC values were similar to control group.Conclusion: These results suggest that the role of CYP3A5 enzyme has to be taken into account for probable drug interactions and sufficient immunosuppression in patients who are treated with tacrolimus