To understand the mechanism underlying the highly liver-selective distribution of pitavastatin, uptake experiments were performed using rat hepatocytes. The uptake of pitavastatin into rat hepatocytes is carrier-mediated and involved nonspecific diffusion in the presence of Na(+). The michaelis constant (K(m)) was 26.0 micromol/L, maximal uptake velocity (V(max)) was 3124 pmol/min/mg protein, and non-specific uptake (P(dif)) was 1.16 microL/min/mg protein. There were no remarkable differences in these kinetic parameters between the presence and absence of Na(+). Experiments using metabolic inhibitors revealed that energy-dependent systems contribute to the uptake of pitavastatin in the liver. Some organic anions reduced the uptake into rat hepatocytes in a concentration-dependent manner. The observed rates of inhibition of pitavastatin uptake by BSP, TCA and pravastatin were compared with the predicted rates. The predicted values were calculated, assuming that BSP, TCA and pravastatin inhibit the uptake of pitavastatin in a competitive manner. The observed inhibition by BSP and TCA was similar to that predicted, but the observed inhibition by pravastatin was considerably less than that predicted. In conclusion, most of the pitavastatin taken up into the liver is transported by multiple carrier-mediated transporters such as Na(+)-independent multispecific anion transporters and energy-dependent transporters. In addition, these systems for pitavastatin may have features in common with the BSP and TCA transport system, and may partially involve the pravastatin transport system.