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 inhibitor, pravastatin is actively taken up by isolated rat hepatocytes via a multispecific anion transporter (Yamazaki et al., Am. J. Physiol. 264, G36-44, (1993)). We further attempted the quantitative evaluation of this uptake in different experimental systems. Methods. We have quantified the initial uptake of pravastatin by both primary cultured hepatocytes and by isolated perfused rat liver using the multiple indicator dilution (MID) method. Results. The permeability surface area product for the influx (PSinf) of pravastatin evaluated in MID study was comparable with those reported previously in isolated rat hepatocytes and in vivo. Furthermore, the highly concentrative uptake (influx clearance >>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 pravastatin showed a decrease with time in culture (0-96 hr). The Vmax for uptake diminished with increasing time in culture, while no significant change was observed in both Km and nonspecific diffusion clearance. Conclusions. The MID method in isolated perfused liver which maintains the spatial and anatomical architecture can be used to quantitatively evaluate 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.