Cellular uptake of fluvastatin, an inhibitor of HMG‐CoA reductase, by rat cultured hepatocytes and human aortic endothelial cells

Aims To clarify the mechanism for cellular uptake of fluvastatin (FV) into rat primary cultured hepatocytes and human aortic endothelial cells (HAEC). Methods Rat primary cultured hepatocytes and Endocell‐AO as normal human aortic endothelial cells were used. Effects of incubation time, concentration‐ and temperature‐dependency on cellular FV uptake were investigated after incubation with [14C]‐FV and its enantiomers, (+)‐FV and (−)‐FV. Rat primary cultured hepatocytes were washed with either Na+‐containing buffer or Na+‐free buffer and incubated with metabolic inhibitors or bile acids. Intracellular radioactivity was measured by liquid scintillation counting. The determination of intracellular unchanged FV and its enantiomers was carried out by stereospecific h.p.l.c. Results In rat cultured hepatocytes, concentration‐ and temperature‐dependent saturable uptake of [14C]‐FV was observed (Km=37.6 μm, V max=869 pmol (mg protein)−1 min−1 ), suggesting a specific uptake mechanism. The uptake of each enantiomer also showed a specific uptake mechanism as observed for the racemate with no difference between enantiomers; (+)‐FV, Km=38.5 μm, V max=611 pmol (mg protein)−1 min−1, (−)‐FV, Km=41.5 μm, V max=646 pmol (mg protein)−1 min−1. In the presence of cholate and taurocholate, the uptake of FV was inhibited by 39–46%. Pravastatin inhibited FV uptake by 29%. In the absence of Na+, the uptake of FV was markedly inhibited 91–96% by bile acid. The uptake of FV into HAEC at 37° C and 4° C increased with the concentration of FV, but no saturable uptake was observed. Conclusions FV transport system may be, at least in part, Na+‐ and ATP‐dependent, and may have some features in common with the bile acid transport system and the organic anion transport system. Since saturable uptake was not observed in HAEC, FV appears to be taken up into these cells mainly via nonspecific simple diffusion.