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  • 1
    Electronic Resource
    Electronic Resource
    Evaluation of the Uptake of Pravastatin by Perfused Rat Liver and Primary Cultured Rat Hepatocytes (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1741-1745 
    Details
    ISSN: 1573-904X
    Keywords: multiple indicator dilution method ; primary cultured hepatocytes ; carrier-mediated uptake ; active transport ; HMG-CoA reductase inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract 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 〉〉 efflux 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016226024587
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  • 2
    Electronic Resource
    Electronic Resource
    Pravastatin, an HMG-CoA Reductase Inhibitor, Is Transported by Rat Organic Anion Transporting Polypeptide, oatp2 (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 904-908 
    Details
    ISSN: 1573-904X
    Keywords: Pravastatin ; HMG-CoA reductase inhibitor ; organic anion transporter ; oatp2 ; hepatic transport
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. We previously demonstrated the HMG-CoA reductase inhibitor, pravastatin, is actively taken up into isolated rat hepatocytes through multispecific organic anion transporters. The present study examined whether a newly cloned organic anion transporting polypeptide (oatp2) transports pravastatin. Methods. We investigated functional expression of oatp2 in Xenopus laevis oocytes, to examine [14C] pravastatin uptake. Results. [14C] Pravastatin (30 μM) uptake into oatp2 cRNA-injected oocytes was 40 times higher than that of water-injected control oocytes. The oatp2-mediated pravastatin uptake was Na+-independent and saturable. The Michaelis-Menten constant was 37.5 ± 9.9 μM, a level comparable to that obtained in isolated rat hepatocytes in our previous study. As is the case with rat hepatocytes, the uptake of pravastatin (30 μM) was inhibited by 300 μM concentrations of taurocholate, cholate, bromosulfophthalein, estradiol-17β-glucuronide, and simvastatin acid, but not by para-aminohippurate. On the other hand, [14C] simvastatin acid (30 μM) uptake of oatp2 cRNA-injected oocytes was not significantly different from that of water-injected oocytes. Conclusions. The cloned oatp2 was identified as the transporter responsible for the active hepatocellular pravastatin uptake.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018838405987
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    Paper (German National Licenses)
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