Background: CYP3A4/5 and p-glycoprotein (PGP) are the major determinants of tacrolimus (Tac) and cyclosporine (CsA) pharmacokinetics. Although these drugs inhibit CYP3A4/5 and PGP, little is known about the extent of inhibition in vivo. The aim of this study was to examine whether Tac and CsA differentially affect in vivo hepatic CYP3A4 activity in renal transplant recipients.
Material/Methods: The N-methyl-[sup]14[/sup] C-Erythromycine Breath Test (EBT) was performed in 12 Tac and 7 CsA treated renal transplant recipients at 1 (n=4) or 3 (n=15) months after transplantation. The cumulative amount of [sup]14[/sup]C-CO[sub]2[/sub] exhaled in one hour expressed as % of the administered dose [sup]14[/sup]C (EBT C[sub]60[/sub] [%]) reflects in vivo hepatic CYP3A4 activity.
Results: There were no significant differences in baseline characteristics (age, weight, time after transplantation, methylprednisolone dose, concomitant medication, creatinine, hematocrit, albumin), except for a significantly higher number of females in the Tac-group (Tac=6/12 vs CsA=0/7, p=0.04). EBT C[sub]60[/sub] was significantly higher in the Tac-group (median EBT C[sub]60[/sub] Tac=1.99% vs CsA=1.45%, p=0.004, Figure 1). Reanalysis excluding 1 month data (median EBT C[sub]60[/sub] Tac=1.99% vs CsA=1.45%, p=0.012) and female patients (median EBT C[sub]60[/sub] Tac=1.95% vs CsA=1.45%, p=0.018) showed similar results. In multivariate regression analysis (stepwise selection) Tac vs CsA was the only variable that was significantly associated with EBT C[sub]60[/sub] (R[sup]2[/sup]=0.38, p=0.005).
Conclusions: Renal transplant recipients treated with tacrolimus have a significantly higher in vivo hepatic CYP3A4 activity early after transplantation as compared to cyclosporine treated patients, indicating a more pronounced CYP3A4 inhibition in vivo by cyclosporine. This finding could be important in daily clinical practice as differences in drug-drug interactions can be expected.

Keywords: P-Glycoprotein, Tacrolimus, Cyclosporine