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Effect of olsalazine on sodium-dependent bile acid transport in rat ileum

  • Intestinal Disorders, Inflammatory Bowel Disease, Immunology, And Microbiology
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Abstract

Olsalazine (OLZ), a relatively new form of 5-aminosalicylic acid (5-ASA), 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 excess BAs reaching the colon, with consequent BA-induced secretory diarrhea. 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), andXenopus laevis oocytes. Segments and everted sacs were treated with 5 mM OLZ for 30 min prior to and throughout 10-min taurocholate (Tc) uptake. Terminal ileal BBMV were used to study the effect of OLZ on sodium-dependent bile acid uptake independent of cellular metabolism. Direct effects on the bile acid carrier were examined usingXenopus laevis oocytes expressing the 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 inhibition 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. In BBMV, OLZ inhibited 45-sec Tc uptake in a dose-dependent manner but did not effect Na-dependentl-alanine uptake. Kinetic analysis revealed a noncompetitive inhibition by 2 mM olsalazine. Olsalazine, 5 mM, also inhibited Na-dependent uptake of Tc into oocytes, which expressed the 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-dependent manner. This inhibition is relatively specific, noncompetitive, and does not require intact cellular mechanisms. This effect of OLZ on ileal function may contribute to the diarrhea frequently observed with this drug.

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Authors and Affiliations

  1. From the Departments of Pediatrics, Research Laboratory of the Center for Pediatric Ileitis and Colitis, North Shore University Hospital-Cornell University Medical College, Manhasset, NY

    Anupama Chawla MD, Peter I. Karl PhD, Rosandra N. Reich, Gopal Narasimhan, Gregory A. Michaud, Stanley E. Fisher MD & Benjamin L. Schneider MD

  2. Department of Pediatrics, Division of Pediatric Gastroenterology/Hepatology, Yale University School of Medicine, New Haven, Connecticut

    Anupama Chawla MD, Peter I. Karl PhD, Rosandra N. Reich, Gopal Narasimhan, Gregory A. Michaud, Stanley E. Fisher MD & Benjamin L. Schneider MD

Authors
  1. Anupama Chawla MD
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  2. Peter I. Karl PhD
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  3. Rosandra N. Reich
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  4. Gopal Narasimhan
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  5. Gregory A. Michaud
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  6. Stanley E. Fisher MD
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  7. Benjamin L. Schneider MD
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Additional information

Supported in part by a grant from Reach Out For Youth with IBD and a gift from Ruth & Leonard Litwin and by grants from the National Institute of Health (DK02076,34989,43509, HD07388, HD20632 and HD27757).

This work was presented in part at the American Gastroenterological Association meeting, Boston, Massachusetts, May 19, 1993.

Address for reprint requests: Dr. Anupama Chawla, Pediatric Gastroenterology, North Shore University Hospital-Cornell University Medical College, 300 Community Drive, Manhasset, New York 11030.

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Chawla, A., Karl, P.I., Reich, R.N. et al. Effect of olsalazine on sodium-dependent bile acid transport in rat ileum. Digest Dis Sci 40, 943–948 (1995). https://doi.org/10.1007/BF02064181

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  • DOI: https://doi.org/10.1007/BF02064181

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