title: Inhibition of the intestinal absorption of bile acids using cationic derivatives: mechanism and repercussions.
abstract: 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 Ki values of 28 and 16 microM, respectively. BAPA-3 reduced Vmax without affecting Km. In contrast, BAPA-6 increased Km, with no effect on Vmax. Uptake of [14C]-GC by the last 10 cm of the rat ileum, perfused in situ over 60 min, 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.
authors.affiliation: Department of Physiology and Pharmacology, Campus Miguel de Unamuno, University of Salamanca, 37007 Salamanca, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Vicens
authors.forename: Rocio I R
authors.initials: RI
authors.lastname: Macias
authors.forename: Oscar
authors.initials: O
authors.lastname: Briz
authors.forename: Alfonso
authors.initials: A
authors.lastname: Rodriguez
authors.forename: Mohamad Y
authors.initials: MY
authors.lastname: El-Mir
authors.forename: Manuel
authors.initials: M
authors.lastname: Medarde
authors.forename: Jose J G
authors.initials: JJ
authors.lastname: Marin
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D007082:Ileum / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D051379:Mice; D029363:Organic Anion Transporters, Sodium-Dependent / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013261:Sterols / Q000494:pharmacology*; D027981:Symporters / Q000502:physiology; D014982:Xenopus laevis
chemical_list: C517363:BAPA-3; C517364:BAPA-6; D001647:Bile Acids and Salts; D029363:Organic Anion Transporters, Sodium-Dependent; D013261:Sterols; D027981:Symporters; C071908:sodium-bile acid cotransporter