NTCP

Importantly, the currently available transporter models only cover a small fraction of all transporters involved in drug disposition. Other than incorporating current stand-alone transporter models into systemic models to directly predict drug pharmacokinetic properties, continued efforts are still needed to investigate other transporters such as MRP, BCRP, NTCP, and OAT, to get a more complete understanding of the drug pharmacokinetic profile. 

NTCP Sodium-dependent taurocholate cotransporting polypeptide... 

Bile acid transporters NTCP, ISBT SLC10A... 

Recently, molecular biology studies have been carried out on hepatic uptake transporters. With regard to the Na+-dependent hepatic uptake of bile acids, Na+-taurocholate cotransporting polypeptide (Ntcp/NTCP) has been cloned from both rodents and humans [14-17]. Ntcp/NTCP accepts bile salts, such as taurocholate and glycocholate, as well as some anionic compounds such as dehydroepian-drosterone sulfate and bromosulfophthalein [16, 18]. However, the presence of unidentified Na+-dependent transporters for anionic drugs (e.g., bumetanide) has also been suggested [19, 20]. 

For equation 12.3-29, we may not be able to use the simplified result in equation 12.3-30, since ntCP may not be constant but depend on fA to investigate this, we form... 

OATP1B1 NTCp OAT2Qst m MRP3 0ATP1B3 NTCP OCT1 NIRP4... 

Trauner, M., Arrese, M., Lee, H., Boyer, J.L. and Karpen, S.J. (1998) Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors. Journal of Clinical Investigation, 101, 2092-2100. 

Although absolute proof is still lacking it seems clear that NTCP is the major sodium-dependent transporter of bile acids, although a minor role for other proteins cannot be excluded. It has now been isolated from rat, mouse, rabbit and human. The rat polypeptide was first expressed in Xenopus laevis oocytes and shown to be a 362 amino acid glycoprotein with 7 or 9... 

The first studies of specificity were carried out using cholate, the glycine and taurine conjugates and taurine conjugates of the dihydroxy bile acids cheno-deoxycholate and ursodeoxycholate. Kramer and colleagues prepared plasma membrane vesicles from rat liver and compared bile-acid transport with values from CHO cells stably expressing NTCP. This work established that transport by the liver enzyme was maximal when 2 hydroxyls were present,... 

Figure 2.1 Hepatocyte basolateral bile acid transporters. Protein-bound bile acids returning in portal blood are taken up by the hepatocyte via the sodium taurocholate co-transporting polypeptide (NTCP) and organic-anion-transporting polypeptide (OATP). In cholestasis bile acids may be returned to blood by the multi-drug-resistance-associated protein 3 (MRP3).

Both specificity studies confirmed that bromosulphthalein (BSP) competitively inhibited taurocholate transport by NTCP and OATP. This is in conflict with reports that BSP transport was not sodium dependent, suggesting that OATP was responsible.The reason for this dilference is not clear but may reflect dilferences in the approaches, using isolated rat hepatocytes or transfection to produce cells that stably express the protein. Choice of cell line may also be important as expression of MEH also showed dilferences, with no demonstrable Na" -dependent transport of taurocholate in Syrian hamster kidney cells or oocytes but Na" -dependent transport was shown in Mardin-Darby canine... 

OATP expression is controlled by similar nuclear factors to NTCP but, unlike NTCP, the activity is down-regulated by phosphorylation of serine... 

Leslie, E.M. et al. (2007) Differential inhibition of rat and human Na + -dependent taurocholate cotransporting polypeptide (NTCP/SLCIOAI) by bosentan a mechanism for species differences in hepatotoxicity. Journal of Pharmacology and Experimental Therapeutics, 321 (3), 1170-1178. 

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