Canalicular transporter

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. 5.2 Schematic showing key sinusoidal and canalicular transport proteins and their substrate characteristics.

Hayes JH, Soroka CJ, Rios-Velez L, et al. Hepatic sequestration and modulation of the canalicular transport of the organic cation, daunorubicin, in the Rat. Hepatology 1999 29(2) 483 t93. 

Another sinusoidal transporter catalyzes Na+-independent uptake of organic anions and is instrumental for biliary clearance of glucuronidated and sulfated steroids, the diagnostic chemical bromosulfophthalein (BSP) and possibly bilirubin. Canalicular transport of glucuronidate and GSH conjugates is coupled to ATP... 

Figure 28.3. Transport of bile acids and other constituents across the hepatocyte. The Na+ dependent bile salt (taurocholate) transporter (BA-) is shown on the sinusoidal membrane that utihzes the Na+ gradient maintained by the NAK pump, shown here on the lateral aspect of the plasmalemma. Bile salt transcellular transport involves microtubules, which then dehver substrate to the canahcular bile salt transporter (1). Bilary excretion of GSH, gluc-uronate (GluA), and sulfate conjugates of compounds such as 17P-estradiol (E2), bilirubin, and bromosulfothalein (BSP) is catalyzed by the multispecific organic anion transporter (MOAT 2). Both 1 and 2 are members of the ABC family of ATP-dependent transporters that also includes P-glycoprotein (3), another canalicular transporter catalyzing excretion of hpophihc compounds such as the chemotherapeutic drug, daunorubicin.

Cholestatic Mechanisms Sinusoidal transporters and canalicular transporters are involved in the movement of bile salts from the sinusoids into the canahculi. Within the hepatocyte, transcytosis is mediated by cytoskeletal transport mechanisms. Bile is moved within the canaliculi through actions of the hepatocyte cytoskeleton causing contraction of the canalicular lumina (Treinen-Moslen, 2001). Xenobiotics acting on any of the above systems may influence bile transport and secretion. 

Inhibition of bile acid transport More than 100 medicaments can cause intrahepatic cholestasis. In this case, the canalicular transport mechanisms are impaired. The retained bile acids damage the cells. 

Lossinsky AS, Vorbrodt AW, Wisniewski HM (1983) Ultracyto-chemical studies of vesicular and canalicular transport structures in the injured mammalian blood-brain barrier. Acta Neuropathol (Berl) 61 239-245. 

Canalicular transport of reduced glutathione in normal and mutant Eisai hyperbilirubinemic rats. The Journal of Biological Chemistry, 267, 1667-1673. 

For several therapeutic purposes, it is desirable to aim for excretion of drugs via canalicular transporters. First, delivery of drugs to bile can promote drug action in the biliary tree. Second, it may be attractive in terms of pharmacokinetics to have a drug that undergoes enterohepatic circulation that involves transport via canalicular transporters. Examples of these applications will be discussed hereafter. 

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. 

Biliary GSH excretion occurs through an electrogenic Na+-independent ATP-independent canalicular transport system which is czs-inhibited and trans-stimulated by certain organic anions and induced by phenobarbital [67]. 

Garcfa-Ruiz C, Morales A, Col ell A, Rodes J, Yi JR, Kaplowitz N, Fernandez-Checa JC (1995) Evidence that the rat hepatic mitochondrial carrier is distinct from the sinusoidal and canalicular transporters for reduced glutathione. Expression studies in Xenopus laevis oocytes. J Biol Chem 270 15946-9... 

Besides MRP2, the other important canalicular transporter in terms of biliary drug excretion is MDRl (Pgp). This widely studied transporter plays a major role in the excretion of numerous endogenous and exogenous compounds by the liver. Drug substrates for Pgp include anticancer agents, antivirals. 

Human Canalicular Transport Proteins (Biliary Transport)... 

Figure 9.9 Human hepatic canalicular transport proteins. Important canalicular transport proteins are depicted with arrows denoting the direction of transport and ATP-dependent transporters designated by . Typical substrates are listed (OA , organic anions OC", organic cations TC, taurocholate MX, mitoxantrone). With kind permission from Springer Science +Business Media Pharmaceutical Research, The complexities of hepatic drug transport Current knowledge and emerging concepts, volume 21, 2004, pp.719-735, P. Chandra and K.L.R. Brouwer, Figure 2.

Elferink RPJO, De Haan J, Lambert KJ, Hagey LR, Hofmann AF, Jansen PLM. Selective hepatobiliary transport of nordeoxycholate side chain conjugates in mutant rats with a canalicular transport defect. Hepatology (Philadelphia, PA, United States) 1989 9 861-865. 

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