BILE-ACIDS AS DRUGS - PRINCIPLES, MECHANISMS OF ACTION AND FORMATIONS

Bile acid therapy is based on the use of bile acid agonists or bile ac id antagonists. Bile acid agonists consist of bile acids or their deri vatives. They are used for two purposes. The first is to correct a def iciency in bile acids because of defective biosynthesis or intestinal conservation and thereby to restore bile acid function, This rationale may be termed replacement therapy, The second is to alter the composi tion of circulating bile acids and thereby to modulate cholesterol met abolism and/or decrease the cytotoxicity of the circulating bile acid pool. This rationale may be termed displacement therapy, Administratio n of chenodeoxycholic (CDCA) and/or ursodeoxycholic (UDCA) decreases b iliary secretion of cholesterol leading to secretion of bile that is u nsaturated in cholesterol and gradual dissolution of cholesterol galls tones, Administration of UDCA to patients with chronic cholestatic liv er disease lo,vers the proportion of endogenous cytotoxic dihydroxy bi le acids in the circulating bile acids, improves liver tests, and dela ys liver failure. Bile acid antagonists act to decrease intestinal con servation of bile acids either by sequestering bile acids in the intes tinal lumen or by inhibiting bile acid transport by the heal enterocyt e. For therapy, CDCA is administered as the protonated acid and is wel l absorbed. UDCA is also administered as the protonated acid, but abso rption is incomplete, Complete absorption can be obtained using the so dium salt of UDCA in a capsule with a pa-sensitive enteric coating. Th e taurine conjugate of UDCA is administered as the protonated sulfonic acid, and its absorption requires a carrier mechanism; however, it is likely to undergo rapid deconjugation during enterohepatic cycling, l iberating UDCA which can be passively absorbed. The future is likely t o see the development of synthetic bile acid analogues that will repla ce the natural bile acids as potent and safe enterohepatic drugs.