EVALUATION OF THE UPTAKE OF PRAVASTATIN BY PERFUSED-RAT-LIVER AND PRIMARY CULTURED RAT HEPATOCYTES

Purpose. We have already demonstrated that the HMG-CoA reductase inhib itor, pravastatin is actively taken up by isolated rat hepatocytes via a multispecific anion transporter (Yamazaki et al., Am. J. Physiol. 2 64, G36-44, (1993)). We further attempted the quantitative evaluation of this uptake in different experimental systems. Methods. We have qua ntified the initial uptake of pravastatin by both primary cultured hep atocytes and by isolated perfused rat liver using the multiple indicat or dilution (MID) method. Results. The permeability surface area produ ct for the influx (PSinf) of pravastatin evaluated in MID study was co mparable with those reported previously in isolated rat hepatocytes an d in vivo. Furthermore, the highly concentrative uptake (influx cleara nce >>eMux clearance) of pravastatin was confirmed by kinetic analysis of the dilution curves obtained in the MID study. On the other hand, the uptake by primary cultured cells was significantly lower than that by isolated cells, and the ability of hepatocytes to take up pravasta tin showed a decrease with time in culture (0-96 hr). The Vmax for upt ake diminished with increasing time in culture, while no significant c hange was observed in both Km and nonspecific diffusion clearance. Con clusions. The MID method in isolated perfused liver which maintains th e spatial and anatomical architecture can be used to quantitatively ev aluate the initial uptake of pravastatin. Furthermore, the ability of hepatocytes to take up pravastatin is diminished in culture with time and this is caused by a decrease in Vmax.