2000 Volume 15 Issue 3 Pages 219-225
The fully synthetic and novel 3-hydroxy-3-methylglutaryl-coenzyme A (HMG—CoA) reductase inhibitor, cerivastatin, was found to show highly liver-selective distribution in rats. To elucidate the mechanism on such organ-selective distribution, the possibility of the carrier-mediated uptake of cerivastatin was investigated using primary cultured rat hepatocytes (cultured for 4 h).
Cerivastatin was found to be taken up into hepatocytes in a saturated manner, and kinetic evaluation revealed that the Michaelis-Menten constant (Km) and the maximum uptake velocity (Vmax) were 5.86μM and 260 pmol/min/mg protein, respectively. Almost comparable kinetic parameters were obtained in the absence of Na+ (Km=4.68 μM, Vmax=268 pmol/min/mg protein), indicating that the cerivastatin uptake is Na+-independent. Kinetic estimation also revealed that the specific uptake clearance accounted for approximately 70 ?? 80% of the total uptake clearance. Based on such a high specific uptake clearance, an extremely high cell-to-medium concentration ratio was observed at equilibrium after 60-min incubation.
A metabolic inhibitor, 2, 4-dinitrophenol, diminished the total uptake clearance of cerivastatin to about 41% of the control value, demonstrating an ATP-dependent uptake. Bromosulfophtalein, an organic anion taken up via Na+-independent multispecific anion transporters, exhibited the concentration-dependent inhibition toward the cerivastatin uptake. Cholate and taurocholate, substrates for organic anion transporting polypeptides (oatp) 1, inhibited the cerivastatin uptake into isolated rat hepatocytes. In addition, pravastatin, substrate for oatp2, also reduced the total uptake clearance of cerivastatin.
In conclusion, cerivastatin undergoes the hepatocellular uptake via Na+-independent multispecific anion transporters, causing a highly liver-selective distribution. Inhibition studies also suggested that oatp 1 and oatp 2 would be responsible for the active hepatocellular uptake of cerivastatin.
