Hepatocyte efflux transporter

It is also important to predict the in vivo biliary excretion clearance in humans, and for this purpose MDCK II cell lines expressing both uptake and efflux transporters may be used (Fig. 12.3) [92, 93]. It has been shown that MRP2 is expressed on the apical membrane, whereas OATP2 and 8 are expressed on the basolateral membrane after cDNA transfection (Fig. 12.3) [92, 93]. The transcellular transport across such double-transfected cells may correspond to the excretion of ligands from blood into bile across hepatocytes. Indeed, the vectorial transport from the basal to apical side was observed for pravastatin only in OATP2- and MRP2-expressing... 

A more recent example of this technique has been the study on human absorption characteristics of fexofenadine [109], Fexofenadine has been shown to be a substrate for P-gp in the in vitro cell lines its disposition is altered in knockout mice lacking the gene for MDRla, and co-administration of P-gp inhibitors (e.g. ketoconazole and verapamil) was shown to increase the oral bioavailability of fexofenadine [110-113], Hence, it is suggested that the pharmacokinetics of fexofenadine appears to be determined by P-gp activity. In the human model, the intestinal permeability estimated on the basis of disappearance kinetics from the jejunal segment is low, and the fraction absorbed is estimated to be 2% [114], Co-administration of verapamil/ketoconazole did not affect the intestinal permeability estimates however, an increased extent of absorption (determined by de-convolution) was demonstrated. The increased absorption of fexofenadine was not directly related to inhibition of P-gp-mediated efflux at the apical membrane of intestinal cells as intestinal Peff was unchanged. Furthermore, the effect cannot be explained by inhibition of intestinal based metabolism, as fexofenadine is not metabolised to any major extent. It was suggested that this may reflect modulation of efflux transporters in hepatocyte cells, thereby reducing hepatobiliary extraction of fexofenadine. 

FIGURE 34.6 Distribution of the main drag ABC (green) and SLC (pink) transporters on the basolateral (sinusoid) and apical (bile canaliculus) membranes of the human hepatocytes. SLC transporters at the basolateral membrane mainly define active hepatic uptake whereas ABC transporters at the basolateral and bile canaliculus membranes efflux drugs and their metabolites in blood or bile, respectively. 

Transporters also contribute to the drug distribution in certain tissues. Most statins are taken up into the hepatocytes by OATP, excreted into the bile by efflux transporters, and reabsorbed in the intestine, thereby effectively undergoing enterohepatic circulation and maintaining high concentrations in... 

The IC50 and of transporter inhibitors can be determined using selective transporter substrate by in vitro assays. For uptake transporters, hepatocyte, transporter transfected cells, oocytes, and yeast have been used as in vitro models for efflux transporter, Caco-2 cells, and transporter transfected cells and membranes are commonly used models. 

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