Transport clearance, transcellular

Figure 6 Directional transport of pravastatin in Oatplb2/Mrp2 double transfectants in the apical direction (A), and comparison of in vivo biliary excretion clearance and in vitro transcellular transport clearance across the double transfectant (B). (A) Transcellular transport across the monolayers of MDCK II cells was determined in the basal-to-apical and the opposite direction. (B) The x axis represents CLint determined in vitro multiplied by /B and the scaling factor, and the y axis represents the in vivo biliary clearance defined for the blood ligand concentrations. The symbol ( ) represents data whose x axis values were corrected for the scaling factor (a = 17.9). The solid line represents the theoretical curve, and the symbol (o), the observed data. Source From Ref. 59.

Sasaki M, Suzuki H, Aoki J, Ito K, Meier PJ and Sugiyama Y. Prediction of in vivo biliary clearance from the in vitro transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II monolayer expressing both rat organic anion transporting polypeptide 4 and multidrug resistance associated protein 2. Mol Pharmacol 2004 66 450-9. 

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... 

In two other cases in which clarithromycin increased serum digoxin concentrations there was an associated reduction in the rate of renal digoxin clearance, which may be another mechanism for this interaction (272). The authors hypothesized that clarithromycin inhibited P glycoprotein. This was supported by the observation of a concentration-dependent effect of clarithromycin on in vitro transcellular transport of digoxin. 

Figure 11.5 Vectorial transcellular transport of pravastatin, its basal-to-apical transcellular drugs in double-transfected cells, (a) The double- transport is significantly higher compared to the transfected cells expressing OATP1B1 (uptake apical-to-basal transport [177]. (b) Prediction of transporter) on the basal side and MRP2 (efflux in vivo biliary clearance of several bisubstrates of transporter) on the apical side have been rat Oatplb2 and Mrp2 from their in vitro...

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