Membrane sinusoidal

Suzuki, H., Sugiyama, Y., Transport of drugs across the hepatic sinusoidal membrane sinusoidal drug influx and efflux in the liver, Semin. Liver Dis. 2000, 20, 251-263. 

IV basement 1(1V) 1398 112, 345, 556 Basement membrane, sinusoid Polygonal meshwork... 

Since this facilitated transport system allows the equilibrium of bilirubin across the sinusoidal membrane of the hepatocyte, the net uptake of bilirubin will be dependent upon the removal of bilirubin via subsequent metabolic pathways. 

The red blood cell must be able to squeeze through some tight spots in the microcirculation during its numerous passages around the body the sinusoids of the spleen are of special importance in this regard. For the red cell to be easily and reversibly deformable, its membrane must be both fluid and flexible it should also preserve its biconcave shape, since this facilitates gas exchange. Membrane lipids help determine membrane fluidity. Attached to the inner aspect of the membrane of the red blood cell are a number of peripheral cytoskeletal proteins (Table 52-6) that play important roles in respect to preserving shape and flexibility these will now be described. 

Zimmerli, B., J. Vaiantinas, and P. J. Meier. Multispecificity of Na+-dependent taurocholate uptake in basolateral (sinusoidal) rat liver plasma membrane vesicles. J. Pharmacol. Exp. Ther. 1989, 250, 301-318. 

The liver plays an important role in determining the oral bioavailability of drags. Drag molecules absorbed into the portal vein are taken up by hepatocytes, and then metabolized and/or excreted into the bile. For hydrophilic drugs, transporters located on the sinusoidal membrane are responsible for the hepatic uptake [1, 2]. Biliary excretion of many drags is also mediated by the primary active transporters, referred to as ATP-binding cassette transmembrane (ABC) transporters, located on the bile canalicular membrane [1, 3-5], Recently, many molecular biological... 

MDCK II cells (Fig. 12.3) [93], Kinetic analysis revealed that the Km value for transcellular transport (24 pM) was similar to the Km for OATP2 (34 pM) [93], Moreover, the efflux across the bile canalicular membrane was not saturated under these experimental conditions. These in vitro observations are consistent with in vivo experimental results in rats which showed that the rate-determining process for the biliary excretion of pravastatin is uptake across the sinusoidal membrane. By normalizing the expression level between the double transfectant and human hepatocytes, it might be possible to predict in vivo hepatobiliary excretion. 

Effect of Drugs on the Activity of Transporters Located on the Sinusoidal Membrane... 

If the unbound drug concentrations in plasma are higher than their K values on the transporters, then transporter function may be significantly affected [106], Following a pharmacokinetic analysis of the effect of probenecid on the hepatobiliary excretion of methotrexate, it has been shown the extent of an in vivo drug-drug interaction can be quantitatively predicted from the kinetic parameters for transport across the sinusoidal and bile canalicular membranes determined in vitro [107]. 

Kullak-Ublick, G. A., Regulation of organic anion and drug transporters of the sinusoidal membrane, J. Hepatol. 1999, 31, 563-573. 

Hepatocytes make up 60-70% of the total number of liver cells. They have a well-organized intracellular structure with huge numbers of cell organelles to maintain the high metabolic profile. At the apical side or canalicular membrane the cell is specialized for the secretion of bile components. There are several ATP-dependent transport carriers located on this side of the membrane, which transport bile salts, lipids and xenobiotics into the canaliculus. On the sinusoidal side, the cells specialize in uptake and secretion of a wide variety of components. To increase the surface of the membrane for this exchange with the bloodstream, the sinusoidal domain of the membrane is equipped with irregular microvilli. The microvilli are embedded into the fluid and matrix components of the space of Disse and are in close contact with the sinusoidal blood because of the discontinuous and fenestrated SECs. To facilitate its metabolic functions numerous membrane transport mechanisms and receptors are situated in the membrane. 

Organic anions have frequently been implicated as substrates for transporters in the sinusoidal membrane of the liver. This was illustrated for a series of TxRAs, where hepatic uptake was identified as the rate-determining step in the clearance process [22]. A representative compound from this series, UK-147,535 (Figure 9.3), was progressed to clinical trials [23]. It is thus possible to contrast clearance of this compound between a number of species including man (Figure 9.4). 

As observed in Figure 9.4 the intrinsic clearance (as represented by oral unbound clearance CIqu) of UK-147,535 shows an allometric relationship between the rat, dog and man. This would indicate that the transporter protein involved is conserved across these species and has similar affinity. However, marked reduction in clearance in the rabbit suggests the absence, or marked alteration, of the responsible protein in the hepatic sinusoidal membrane of this species. This finding may explain the common observation of reduced biliary excretion of acidic compounds in rabbits compared to other species [24, 25]. 

Plasma Membranes and Derived Transporters Measurement of transported calcium in synaptosomes, 174, 3 glutamate accumulation into synaptic vesicles, 174, 9 identification of bile acid transport protein in hepatocyte sinusoidal plasma membranes,... 

LIVER Use of isolated perfused liver in studies of biological transport processes, 192, 485 measurement of unidirectional calcium ion fluxes in liver, 192, 495 preparation and specific applications of isolated hepatocyte couplets, 192, 501 characterizing mechanisms of hepatic bile acid transport utilizing isolated membrane vesicles, 192, 517 preparation of basolateral (sinusoidal) and canalicular plasma membrane vesicles for the study of hepatic transport processes, 192, 534. 

The passage of most foreign compounds from the blood into the liver normally is not restricted because the endothelium of the hepatic blood sinusoids behaves as a porous membrane. Hence, drugs with molecular weights lower than those of most protein molecules readily reach the hepatic extracellular fluid from the plasma. A number of compounds are taken up into the liver by carrier-mediated systems, while more lipophilic... 

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