EFFECT OF OLSALAZINE ON SODIUM-DEPENDENT BILE-ACID TRANSPORT IN RAT ILEUM

Olsalazine (OLZ), a relatively new form of 5-aminosalicylic acid (5-AS A), is being used for the treatment of colitis. A major side effect of olsalazine is diarrhea, reported in 12-25% of patients. One suggested mechanism for this side effect is enhanced ileal water and electolyte secretion. We propose that OLZ may also inhibit ileal bile acid (BA) transport, resulting in choleretic diarrhea. This would result in exce ss BAs reaching the colon, with consequent BA-induced secretory diarrh ea. Therefore, we studied the effect of OLZ on rat ileal absorption of taurocholate. BA uptake was determined in rat ileal segments, everted sacs, brush border membrane vesicles (BBMV), and Xenopus laevis oocyt es. Segments and everted sacs were treated with 5 mM OLZ for 30 min pr ior to and throughout 10-min taurocholate (Tc) uptake. Terminal ileal BBMV were used to study the effect of OLZ on sodium-dependent bile aci d uptake independent of cellular metabolism. Direct effects on the bil e acid carrier were examined using Xenopus laevis oocytes expressing t he cloned apical rat ileal BA transporter. In ileal segments 5 mM OLZ inhibited 10-min Tc uptake by 69.4 +/- 8.8% (P < 0.01) (N = 10 animals ). Increasing concentrations of OLZ resulted in a dose-dependent inhib ition of Tc uptake. Ten-minute Tc uptake with 0.5, 1.0, 2.0, 2.5, and 5 mM OLZ was inhibited by 13.5, 39.6, 49.7, and 70.5%, respectively. I n BBMV, OLZ inhibited 45-sec Tc uptake in a dose-dependent manner but did not effect Na-dependent L-alanine uptake. Kinetic analysis reveale d a noncompetitive inhibition by 2 mM olsalazine. Olsalazine, 5 mM, al so inhibited Na-dependent uptake of Tc into oocytes, which expressed t he rat ileal sodium-dependent bile acid transporter (8.0 +/- 3.7 vs 2. 6 +/- 2.0 pmol/oocyte/hr, P < 0.001). OLZ inhibits sodium-dependent Tc uptake and transmucosal transport in the rat ileum in a dose-dependen t manner. This inhibition is relatively specific, noncompetitive, and does not require intact cellular mechanisms. This effect of OLZ on ile al function may contribute to the diarrhea frequently observed with th is drug.