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 conjugation of xenobiotics with bile acids facilitates their transfer to hepatocytes and ileal enterocytes. In this study L-alanine and 2 biooligomers, the tetrapeptide L-(ala)(4) and a 15 mer oligodeoxynucleotide (ODN) were coupled covalently via linker molecules to the 3-position of bile acids. The L-alanine-coupled bile acid conjugates were rapidly taken up by the liver and efficiently eliminated into bile. These compounds mimicked hepatic transport of bile acids. Also in case of the tetrapeptide (ala)(4), bile acid conjugation significantly improved hepatic and intestinal cell uptake and rendered the peptide conjugate resistant to peptidases. Because uptake by isolated hepatocytes 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 case of the 15 mer ODN, normal and bile acid-conjugated oligodeoxynucleotide appeared intact in bile but without marked improvement of hepatocellular uptake and biliary elimination. We conclude that bile acids can deliver small peptides to gut and parenchymal liver cells via bile acid transport pathways, whereas in the case of oligonucleotides an attached bile acid was not sufficient to shuttle them successfully into hepatocytes.
Petzinger
E
E
Institute of Pharmacology and Toxicology, Justus-Liebig-University Giessen, Giessen, Germany. ernst.petzinger@vetmed.uni-giessen.de
Wickboldt
A
A
Pagels
P
P
Starke
D
D
Kramer
W
W
D000409:Alanine / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism / Q000502:physiology*; D001647:Bile Acids and Salts / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D006913:Hydroxysteroid Dehydrogenases; D007583:Jejunum / Q000502:physiology; D007700:Kinetics; D008099:Liver / Q000502:physiology*; D008297:Male; D008562:Membrane Glycoproteins; D008657:Metabolic Clearance Rate; D009838:Oligodeoxyribonucleotides / Q000493:pharmacokinetics*; D009842:Oligopeptides / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
D000409:Alanine; D000596:Amino Acids; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D006913:Hydroxysteroid Dehydrogenases; D008562:Membrane Glycoproteins; D009838:Oligodeoxyribonucleotides; D009842:Oligopeptides; C037643:bile acid binding proteins; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)