Hepatobiliary transport of bile acid amino acid, bile acid peptide, and bile acid oligonucleotide conjugates in rats

Uptake of drugs by bile acid carriers could account for the selectivity of drug actions in the gut and liver. We have previously shown that conjugatio n of xenobiotics with bile acids facilitates their transfer to hepatocytes and ileal enterocytes. In this study L-alanine and 2 biooligomers, the tetr apeptide L-(ala)(4) and a 15 mer oligodeoxynucleotide (ODN) were coupled co valently via linker molecules to the 3-position of bile acids. The L-alanin e-coupled bile acid conjugates were rapidly taken up by the liver and effic iently eliminated into bile. These compounds mimicked hepatic transport of bile acids. Also in case of the tetrapeptide (ala)(4), bile acid conjugatio n significantly improved hepatic and intestinal cell uptake and rendered th e peptide conjugate resistant to peptidases, Because uptake by isolated hep atocytes was not dependent on sodium ions and was blocked by ochratoxin A, we assume basolateral transport by an oatp-type bile acid carrier. In the c ase of the 15 mer ODN, normal and bile acid-conjugated oligodeoxynucleotide appeared intact in bile but without marked improvement of hepatocellular u ptake and biliary elimination. We conclude that bile acids can deliver smal l peptides to gut and parenchymal liver cells via bile acid transport pathw ays, whereas in the case of oligonucleotides an attached bile acid was not sufficient to shuttle them successfully into hepatocytes.