Yamazaki M, Kobayashi K, Sugiyama Y
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Biopharm Drug Dispos. 1996 Nov;17(8):645-59. doi: 10.1002/(SICI)1099-081X(199611)17:8<645::AID-BDD986>3.0.CO;2-L.
We have previously demonstrated that the HMG-CoA inhibitor pravastatin is efficiently taken up by the liver via the 'multispecific anion transporter' in an active manner. To further examine the fate of pravastatin within the liver, its biliary excretion was studied in a single-pass liver perfusion system and isolated liver canalicular membrane vesicles (CMVs) using normal (Sprague-Dawley rats; SDRs) and mutant Eisai hyperbilirubinaemic rats (EHBRs). In the liver perfusion experiments, the outflowing drug concentration reached a steady state at 30 min and the extraction ratio was approximately 0.7 in both rat strains. Both the steady state biliary excretion rate and bile flow rate of the EHBR group were 40% of those of SDRS. At steady state, the fraction of unchanged drug in bile was 25-34% in both groups. The concentration ratios of unbound drug in cytosol versus that in sinusoid and of that in bile versus that in cytosol were, respectively, 11 and 87 in SDRs, and 13 and 94 in EHBRs. After correction for the membrane potential (-40 mV in cytosol), the ratios became 49 and 19 in SDR and 58 and 21 in EHBRs, respectively. The finding that all of these values were much larger than unity suggested that active transport occurred from liver to bile, as well as from plasma to liver, in both rat strains. Furthermore, ATP-dependent uptake of pravastatin was clearly observed in CMVs prepared from EHBRs as well as SDRs, whereas the stimulation by ATP of DNP-SG transport in CMVs was observed only in SDRs. It was concluded that pravastatin is excreted into bile in high concentrations and a primary active transport mechanism which is maintained in EHBRs contributes to the biliary excretion of this drug.
我们之前已经证明，HMG-CoA抑制剂普伐他汀通过“多特异性阴离子转运体”以主动方式被肝脏有效摄取。为了进一步研究普伐他汀在肝脏内的去向，我们在单通道肝脏灌注系统以及分离的肝小管膜囊泡（CMV）中，使用正常（Sprague-Dawley大鼠；SDR）和突变的艾塞那高胆红素血症大鼠（EHBR）研究了其胆汁排泄情况。在肝脏灌注实验中，流出药物浓度在30分钟时达到稳态，两种大鼠品系的提取率均约为0.7。EHBR组的稳态胆汁排泄率和胆汁流速均为SDR组的40%。在稳态时，两组胆汁中未变化药物的比例均为25%-34%。SDR组中，胞质溶胶中未结合药物与窦状隙中未结合药物的浓度比以及胆汁中与胞质溶胶中未结合药物的浓度比分别为11和87，EHBR组中则分别为13和94。校正膜电位（胞质溶胶中为-40 mV）后，SDR组的比例分别变为49和19，EHBR组分别变为58和21。所有这些值均远大于1，这一发现表明，在两种大鼠品系中，均存在从肝脏到胆汁以及从血浆到肝脏的主动转运。此外，在从EHBR以及SDR制备的CMV中均清晰观察到普伐他汀的ATP依赖性摄取，而仅在SDR的CMV中观察到ATP对DNP-SG转运的刺激作用。得出的结论是，普伐他汀以高浓度排泄到胆汁中，并且在EHBR中维持的一种原发性主动转运机制有助于该药物的胆汁排泄。
