Role of P-glycoprotein in the hepatic metabolism of tacrolimus

The main objective was to determine the potential effect of P-glycoprotein (P-gp) modulation on hepatic metabolism of tacrolimus, a P-gp and cytochrome P450(CYP) 3A4 substrate, and to investigate various potential factors that may contribute to the interaction between P-gp and CYP. An isolated perfused rat liver system was used to study the hepatic disposition of tacrolimus in the presence of a P-gp inhibitor, GF120918, and a comprehensive pharmacokinetic analysis was conducted. GF120918 significantly decreased mean intrinsic metabolic clearance ( by 86 and 41% based on the well-stirred and tube models, respectively) as well as hepatic clearance ( from 47.3 to 44.2 ml min(-1)). Potential factors that might contribute to these observations, such as the effects of GF120918 on hepatic metabolism or on distribution of tacrolimus, were investigated and found to be negligible. In conclusion, it was shown that P-gp inhibition by GF120918 reduces hepatic clearances of its substrate drugs although the mechanism is yet to be determined.