Bonnaventure Pierre, Pastor Catherine M
Universitaires de Genève, Geneva 1205, Switzerland.
Int J Mol Sci. 2014 Dec 24;16(1):135-47. doi: 10.3390/ijms16010135.
To understand the transport function of drugs across the canalicular membrane of hepatocytes, it would be important to measure concentrations in hepatocytes and bile. However, these concentration gradients are rarely provided. The aim of the study is then to measure these concentrations and define parameters to quantify the canalicular transport of drugs through the multiple resistance associated-protein 2 (Mrp2) in entire rat livers. Besides drug bile excretion rates, we measured additional parameters to better define transport function across Mrp2: (1) Concentration gradients between hepatocyte and bile concentrations over time; and (2) a unique parameter (canalicular concentration ratio) that represents the slope of the non-linear regression curve between hepatocyte and bile concentrations. This information was obtained in isolated rat livers perfused with gadobenate dimeglumine (BOPTA) and mebrofenin (MEB), two hepatobiliary drugs used in clinical liver imaging. Interestingly, despite different transport characteristics including excretion rates into bile and hepatocyte clearance into bile, BOPTA and MEB have a similar canalicular concentration ratio. In contrast, the ratio was null when BOPTA was not excreted in bile in hepatocytes lacking Mrp2. The canalicular concentration ratio is more informative than bile excretion rates because it is independent of time, bile flows, and concentrations perfused in portal veins. It would be interesting to apply such information in human liver imaging where hepatobiliary compounds are increasingly investigated.
为了解药物跨肝细胞胆小管膜的转运功能，测定肝细胞和胆汁中的浓度很重要。然而，这些浓度梯度很少被提供。因此，本研究的目的是测定这些浓度，并确定参数以量化药物在整个大鼠肝脏中通过多药耐药相关蛋白2（Mrp2）的胆小管转运。除了药物胆汁排泄率外，我们还测量了其他参数以更好地定义跨Mrp2的转运功能：（1）肝细胞和胆汁浓度随时间的浓度梯度；（2）一个独特的参数（胆小管浓度比），它代表肝细胞和胆汁浓度之间非线性回归曲线的斜率。这些信息是在灌注了钆贝葡胺（BOPTA）和甲溴菲宁（MEB）的离体大鼠肝脏中获得的，这两种肝胆药物用于临床肝脏成像。有趣的是，尽管BOPTA和MEB具有不同的转运特征，包括胆汁排泄率和肝细胞向胆汁的清除率，但它们的胆小管浓度比相似。相比之下，在缺乏Mrp2的肝细胞中，当BOPTA不排泄到胆汁中时，该比值为零。胆小管浓度比比胆汁排泄率更具信息量，因为它与时间、胆汁流量和门静脉灌注浓度无关。将这些信息应用于越来越多地研究肝胆化合物的人体肝脏成像中将会很有趣。
