Bile Canalicular Transporters

Kitamura, T, Jansen, P., Hardenbrook C., Kamimoto, Y, Gatmaitan, 1.., and Arias, l.M, (1990) Defective ATP-dependent bile canalicular transport of organic anions in mutant (TR ) rats with conjugated hyperbilirubinemia. Proceedings of the Natiorud Academy of Sciences of the United States of America. 87 (9), 3557—3561. 

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... 

It is important to establish an in vitro system which will allow in vivo transport across the bile canalicular membrane to be predicted quantitatively. By comparing the transport activity between in vivo and in vitro situations in isolated bile canalicular membrane vesicles, it has been shown that there is a significant correlation for nine types of substrates [90]. Here, in vivo transport activity was defined as the biliary excretion rate, divided by the unbound hepatic concentration at steady-state, whereas in vitro transport activity was defined as the initial velocity for the transport into the isolated bile canalicular membrane vesicles divided by the medium concentration [90]. Collectively, it is possible to predict in vivo canalicular transport from in vitro experiments with the isolated bile canalicular membrane vesicles. 

Fig. 12.2. Comparison of ATP-dependent transport activity between rats and humans determined in isolated bile canalicular membrane vesicles. Key 1, SN-38 glucuronide (carboxylate) 2, SN-38 glucuronide (lactone) 3, E3040 (6-hydroxy-5,7-dimethyl-2-methyl-amino-4-(3-pyridylmethyl) benzothiazole) glucuronide 4, 170 estradiol-170-D-glucuro-nide 5, grepafloxacin glucuronide 6, leuko-...

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. 

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]. 

Effect of Drugs on the Activity of Transporters Located on the Bile Canalicular Membrane... 

Aoki, J., Suzuki, H., Sugiyama, Y., Quantitative prediction of in vivo biliary excretion clearance across the bile canalicular membrane from in vitro transport studies with isolated membrane vesicles. Abstract of Millennial World Congress of pharmaceutical Sciences, San Francisco, April 16-20, 2000, p. 92. 

Niinuma, K., Kato, Y., Suzuki, H., Tyson, C. A., Weizer, V., Dabbs, J. E., Froehlich, R., Green, C. E., Sugiyama, Y., Primary active transport of organic anions on bile canalicular membrane in humans, Am. J. Physiol. 1999, 276, G1153-G1164. 

In 1991 bile-acid secretion was shown to be energy driven by a 110-kDa glycoprotein that was dependent on ATP. This protein was subsequently characterised as liver ecto-ATPase by Sippel and co-workers. However, while further work with COS cells showed that expression of ecto-ATPase enhanced secretion of bile acids purified canalicular membranes lacking this enzyme efficiently exported bile acids showing that at least one other bile-acid transporter existed. ... 

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. 

Alteration of ER transport, sinusoidal membrane transport, or bile canalicular membrane transport of the glucuronides... 

Excretion Parenchymal cells Bile Canalicular membrane vesicles, transporter expression system... 

Niinuma K, Kato Y, Suzuki H, et al. Sugiyama. Primary active transport of organic anions on bile canalicular membrane in humans. Am J Physiol 1999 276 G1153-G1164. 

Cellular hydration markedly affects epithelial transcellular transport, as exemplified by transcellular bile acid transport in the liver. In the hepatocyte, conjugated bile acids are taken up at the sinusoidal (basolateral) side by an Na+-dependent carrier and are excreted at the canalicular (apical) membrane by means of a specific... 

Figure 22-3. Transport and hepatic metabolism of bilirubin. Bilirubin that is produced in phagocytes is transported to liver as an albumin-bilirubin complex. Uptake into the hepatocytes takes place in liver sinusoids. Within the hepatocyte, bilirubin is transported to the endoplasmic reticulum (microsomes) bound to glutathione S-transferase (GST). Bilirubin is made water soluble by addition of one or two glucuronic acid moieties obtained from UPD-glucuronic acid, catalyzed by bilirubin-UDP-glucuronyltransferase. The product, conjugated bilirubin, is transported across the bile canalicular membrane for secretion into the biliary system, with subsequent movement into the intestines.

FcRn protein is expressed by rat hepatocytes, particularly at the canalicular surface [145] and might facilitate serum-to-bile IgG transport or prevent... 

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