Inhibition of the intestinal absorption of bile acids using cationic derivatives: Mechanism and repercussions.
To pharmacologically interrupt bile acid enterohepatic circulation, two compounds named BAPA-3 and BAPA-6, with a steroid structure and 1 or 2 positive charges, were obtained by conjugation of N-(3-aminopropyl)-1,3-propanediamine with one or two moieties of glycocholic acid (GC). Both BAPA-3 and BAPA-6 inhibited Na(+)-dependent taurocholate (TC) uptake by Xenopus laevis oocytes expressing rat Asbt, with K(i) values of 28 and 16muM, respectively. BAPA-3 reduced V(max) without affecting K(m). In contrast, BAPA-6 increased K(m), with no effect on V(max). Uptake of [(14)C]-GC by the last 10cm of the rat ileum, perfused in situ over 60min, was inhibited to a similar extent by unlabeled GC, BAPA-3 and BAPA-6. However, the intestinal absorption of these compounds was lower (BAPA-6) or much lower (BAPA-3) than that of GC. When administered orally to mice, both compounds (BAPA-3>BAPA-6) reduced the bile acid pool size, which was accompanied by up-regulation of hepatic Cyp7a1 and Hmgcr and intestinal Ostalpha/Ostbeta. A tendency towards a decreased expression of hepatic Ntcp and an enhanced expression of intestinal Asbt was also observed. Serum biochemical parameters were not affected by treatment with these compounds, except for a moderate increase in serum triglyceride concentrations. In sum, our results suggest that these compounds, in particular BAPA-3, are potentially useful tools for inhibiting the intestinal absorption of bile acids in a non-competitive manner.[1]References
- Inhibition of the intestinal absorption of bile acids using cationic derivatives: Mechanism and repercussions. Vicens, M., Macias, R.I., Briz, O., Rodriguez, A., El-Mir, M.Y., Medarde, M., Marin, J.J. Biochem. Pharmacol. (2007) [Pubmed]
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