Bile acid-drug conjugates

The development of lipophillic bile acid-drug conjugates and other bile acid derivatives is an important advance with exciting therapeutic possibilities. 

Wess, G. Kramer, W. Schubert, G. Enhsen, A. Barinhaus, K.-H., Glombik, H. Muller, S. Bock, K. Kleine, H. John, M. Neckermann, G. Hoffmann, A. Synthesis of bile acid drug conjugate potential drug-shuttles for liver-specific targeting. Tetrahedron Lett. 1992, 34, 819-822. 

Glycine participates in the biosynthesis of heme, purines, and creatine and is conjugated to bile acids and to the urinary metabolites of many drugs. 

A7b. Arvan, D. A., and Ritz, A., Measurement of serum albumin by the HABA-dye technique A study of the effect of free and conjugated bilirubin, of bile acids, and of certain drugs. Clin. Chim. Acta 26, 505-516 (1969). 

Receptor-mediated transporters are excipients that serve as substrates to exploit specific receptors present on cell membranes. Examples of various receptors that have been explored for permeation enhancement include bile acids (45), vitamin Bi2 (46), amino acids (47), and folic acid (48). Most of the work in receptor-mediated transporters is conducted via the use of prodrugs. For example, a prodrug of acyclovir conjugated to bile acids was seen to have higher permeability as compared to the original drug, because of receptor-mediated transport of the prodrug via bile acid transporters (49). 

The OATP-C, also referred to as liver specific transporter 1 (LST-1) or OATP2, was cloned by number of groups (8,24,25) and was shown to be exclusively expressed in the basolateral membrane of the liver (25). As with OATP-A, OATP-C has broad substrate specificity and transports bile acids (13), sulfate and glucuronide conjugates (25), thyroid hormones (13), and peptides (16), and drugs such as pravastatin (24), methotrexate (26), and rifampin (27). Given its liver-specific expression and broad substrate... 

Figure 28.3. Transport of bile acids and other constituents across the hepatocyte. The Na+ dependent bile salt (taurocholate) transporter (BA-) is shown on the sinusoidal membrane that utihzes the Na+ gradient maintained by the NAK pump, shown here on the lateral aspect of the plasmalemma. Bile salt transcellular transport involves microtubules, which then dehver substrate to the canahcular bile salt transporter (1). Bilary excretion of GSH, gluc-uronate (GluA), and sulfate conjugates of compounds such as 17P-estradiol (E2), bilirubin, and bromosulfothalein (BSP) is catalyzed by the multispecific organic anion transporter (MOAT 2). Both 1 and 2 are members of the ABC family of ATP-dependent transporters that also includes P-glycoprotein (3), another canalicular transporter catalyzing excretion of hpophihc compounds such as the chemotherapeutic drug, daunorubicin.

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