RELATIONSHIP BETWEEN STRUCTURE AND INTESTINAL-ABSORPTION OF BILE-ACIDS WITH A STEROID OR SIDE-CHAIN MODIFICATION

A structure-activity relationship for bile acid (BAI intestinal absorp tion is known to exist. To better understand the BA structural require ments for optimal BA intestinal absorption, rabbit ileal perfusion stu dies were performed. Unconjugated BA: Ursodeoxycholic (UDCA) and ursoc holic acid (UCA) with methyl (6MUDCA and 6MUCA) or fluoro group (6FUDC A and 6FUCA) in the 6 position and UCA with a methyl group in 23 posit ion (23MUCA) were compared with unconjugated UDCA, UCA, deoxycholic (D CA), chenodeoxycholic (CDCA), hyocholic (HCA), and hyodeoxycholic (HDC A) acid. BA lipophilicity was evaluated by their octanol-M,ater partit ion coefficient. Conjugated BA: Taurine-conjugated UDCA and UCA with a methyl group in the 23 position (T23MUDCA and T23MUCA) were compared with the corresponding taurine-conjugated natural analogs, An analog o f glycine-conjugated UDCA with the C24 amide bond replaced by a -CO-CH 2- in the 24 position (24PUDCA) was studied and results were compared with the natural form (GUDCA). Unconjugated BA absorption was dose dep endent (i.e., passive) and followed their lipophilicity: DCA > 6MUDCA > CDCA > HDCA > UDCA > HCA > 6FUDCA > 6MUCA > 6FUCA > UCA, Conjugated BA absorption was active, and V-max was in the following order: TCA > TUDCA > TUCA > T23MUCA, T23MUDCA > 24PUDCA > GUDCA. 24PUDCA transport was also active and higher than GUDCA. Conclusion: Passive transport i s dependent on BA lipophilicity. Conjugated BAs are actively transport ed and the presence of a 23-C methyl group does not improve transport when compared with the natural analogs. The substitution of the C24 am ide bond with a -CO-CH2- still affords interaction of the BA with the intestinal transport carrier. (C) 1996 by Elsevier Science Inc.