Modified bile acids as carriers for peptides and drugs

• Published in: Journal of controlled release Vol. 46; no. 1-2; pp. 17 - 30
• Main Authors: Kramer, Werner, Wess, Günther, Enhsen, Alfons, Falk, Eugen, Hoffmann, Axel, Neckermann, Georg, Schubert, Gerrit, Urmann, Matthias
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Amsterdam Elsevier B.V 05-05-1997; Elsevier
• Subjects: Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Bile acid transport systems; Biological and medical sciences; Drug targeting; General pharmacology; Medical sciences; Modified bile acids; Oligopeptide transporter; Peptide delivery; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Drug targeting; Bile acid transport systems; Modified bile acids; Oligopeptide transporter; Peptide delivery; Cefalexin; Peptides; Liver; Biological transport; Gut; Molecular interaction; Drug carrier; Permeability; In vitro; Biological activity; In vivo; Antibiotic; Cephalosporin derivatives; Hepatocyte; Membrane transport; Bile acid; Targeted drug; Absorption enhancer; Antibacterial agent; Pharmacokinetics
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/S0168-3659(96)01599-4

For the development of future drugs two aspects are of major importance, a site-specific drug action without adverse side-effects and a preferably oral applicability. The liver has a central role in drug action and many disorders are unique to the liver demanding a liver-specific drug action. In oral drug therapy the small intestine is often the limiting barrier of drug absorption. Bile acids are natural substrates undergoing an enterohepatic circulation involving the liver and the small intestine. This organotropism of bile acids is achieved by specific Na+-dependent transport systems in the plasma membrane of hepatocytes and ileocytes. Di- and tripeptides as well as orally active α-amino-β-lactam antibiotics are intestinally absorbed by a H+/oligopeptide cotransport system of high transport capacity. We, therefore, investigated whether the hepatic and the intestinal bile acid transport systems as well as the intestinal H+/oligopeptide transporter can be used in drug therapy to improve the membrane permeability and intestinal absorption of peptide drugs, to target a drug to the liver and the biliary system and to obtain liver-specific drugs. For this, modified bile acids with linkers of varying structure, length, position and stereochemistry at the steroid nucleus were synthesized and covalently linked to drugs or peptides or alternatively bile acid structural elements were introduced into drugs. To investigate the H+/oligopeptide transporter as a putative peptide delivery system, peptides were covalently attached to the 3′-position of the tripeptide-analogue d-cephalexin. The interaction of these bile acid and cephalexin conjugates with the hepatic and intestinal bile acid and peptide transport systems as well as their pharmacokinetic and pharmacodynamic behaviour was investigated by transport measurements and photoaffinity labeling techniques using membrane vesicles, isolated hepatocytes and in vivo models.