MODIFIED BILE-ACIDS AS CARRIERS FOR PEPTIDES AND DRUGS

For the development of future drugs two aspects are of major importanc e, a site-specific drug action without adverse side-effects and a pref erably 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 li miting barrier of drug absorption. Bile acids are natural substrates u ndergoing an enterohepatic circulation involving the liver and the sma ll 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 alpha-ami no-beta-lactam antibiotics are intestinally absorbed by a H+/oligopept ide cotransport system of high transport capacity. We, therefore, inve stigated whether the hepatic and the intestinal bile acid transport sy stems as well as the intestinal H+/oligopeptide transporter can be use d in drug therapy to improve the membrane permeability and intestinal absorption of peptide drugs, to target a drug to the liver and the bil iary system and to obtain liver-specific drugs. For this, modified bil e acids with linkers of varying structure, length, position and stereo chemistry at the steroid nucleus were synthesized and covalently linke d to drugs or peptides or alternatively bile acid structural elements were introduced into drugs. To investigate the H+/oligopeptide transpo rter as a putative peptide delivery system, peptides were covalently a ttached to the 3'-position of the tripeptide-analogue D-cephalexin. Th e interaction of these bile acid and cephalexin conjugates with the he patic and intestinal bile acid and peptide transport systems as well a s their pharmacokinetic and pharmacodynamic behaviour was investigated by transport measurements and photoaffinity labeling techniques using membrane vesicles, isolated hepatocytes and in vivo models.