Modulation by drugs of human hepatic sodium-dependent bile acid transporter (sodium taurocholate cotransporting polypeptide) activity

Adequate bile flow, maintained in part by the efficient enterohepatic recir culation of bile acids, is critical for normal liver function. One importan t component of this process is the uptake of bile acids from the portal cir culation into hepatocytes by the bile acid uptake transporter sodium tauroc holate cotransporting polypeptide (NTCP). Thus, the expression and function al activity of this transporter may affect the rate of bile acid removal fr om the portal circulation. Accordingly, we assessed NTCP mRNA expression fr om human livers using a sensitive RNase protection assay. In addition, the ability of various bile acids and drugs to inhibit NTCP activity was determ ined using a recombinant vaccinia expression system. A 40-fold interindivid ual variability was found in NTCP mRNA levels determined in eight liver sam ples of disease-free donors. Expressed NTCP exhibited high-affinity, sodium -dependent uptake of taurocholate, and as expected, this was markedly inhib ited by bile acids and organic anions. A number of drugs, including peptido mimetic renin inhibitors, propranolol, cyclosporin, and progesterone, were found to be potent inhibitors, whereas antiarrhythmic agents, including bup ivicaine, lidocaine, and quinidine, were found to enhance NTCP activity. Ac cordingly, these results indicate that large interindividual variability ex ists in NTCP mRNA level and that a number of drugs currently in clinical us e have the potential to interact with and alter NTCP activity, thereby affe cting hepatic bile acid uptake.