Evaluation of 5-aminosalicyltaurine as a colon-specific prodrug of 5-aminosalicylic acid for treatment of experimental colitis

Abstract

We previously reported that 5-aminosalicyltaurine (taurine-conjugated 5-ASA, 5-ASA-Tau) showed a potential as a colon-specific prodrug of 5-aminosalicylic acid (5-ASA) by in vitro evaluation. In this report, we in vivo-evaluated 5-ASA-Tau as a colon-specific prodrug for treatment of experimental colitis. Taurine conjugation of 5-ASA greatly reduced absorption of 5-ASA from the intestine. Oral administration of taurine-conjugated 5-ASA not only increased the colonic delivery efficiency of 5-ASA but also decreased the systemic absorption of free 5-ASA as compared with that of 5-ASA and, moreover, taurine is similarly effective to known colon-specific carriers for 5-ASA, glycine and aspartic acid, suggesting that taurine conjugation is an efficient way to increase the therapeutic effect and to reduce the adverse effects of 5-ASA. Intracolonic treatment with combined 5-ASA/taurine additively ameliorated TNBS-induced colitis rats indicating that taurine acted as not only a promoiety but also a therapeutically active agent. Furthermore, 5-ASA-Tau is slightly more effective than sulfasalazine in alleviating the colonic inflammation induced by TNBS. Taken together, our data suggest that 5-ASA-Tau is a potential colon-specific prodrug of 5-aminosalicylic acid with improved therapeutic activity against inflammatory bowel disease.

Introduction

Inflammatory bowel disease (IBD), which comprises Crohn's disease (CD) and ulcerative colitis (UC), is characterized by relapsing and remitting episodes of active inflammation and chronic mucosal injury (Hugot et al., 1999). Although etiology and pathogenesis of the two major inflammatory bowel diseases remain rather unclear, multiple studies on the etiology of CD and UC have revealed that the development of both diseases is the result of an exaggerated or insufficiently suppressed immune response leading to the onset and continuance of these diseases (Helper and Rex, 2001).

Currently no curative therapeutic agents are available and consequently the therapeutic goal in active IBD is to bring rapidly the patient into a hopefully long lasting remission and to prevent any relapses (Crotty and Jewell, 1992, Ardizzone and Porro, 2002). For induction and maintenance of remission, various drugs can be used including aminosalicylates, glucocorticosteroids and immunomodulators. Among the therapeutic agents, 5-aminosalicylic acid (5-ASA) is the mainstay for inducing and maintaining remission in mild to moderate active UC and CD (Crotty and Jewell, 1992, Lofberg, 2003). However, 5-ASA itself is not adequate to be used for treatment of IBD because it is absorbed rapidly and extensively through the upper intestine before it reaches to the colon (Crotty and Jewell, 1992). In addition, systemically absorbed 5-ASA is reported to induce nephrotic syndrome (Novis et al., 1988). For this reason, 5-ASA is formulated as sustained-release preparations or prodrugs for colon-specific delivery (Sinha and Kumria, 2001, Chourasia and Jain, 2003).

To be colon-specific, a prodrug of 5-ASA should be chemically and biochemically stable and nonabsorbable in the upper intestine so that it could be delivered to the colon in intact form. And the linkage between the drug and the promoiety should be dissociated to liberate the active drug in the colon (Sinha and Kumria, 2001, Sinha and Kumria, 2003). According to these requirements for being colon-specific, we have designed and synthesized colon-specific prodrugs of 5-ASA using amino acids as a promoiety and the data in our previous reports demonstrate that, indeed, N-acyl amide bond derived from 5-ASA and an amino acid (promoiety) is chemically and biochemically stable in the upper intestine and dissociates in the large intestine by the microbial action and moreover, systemic absorption of the prodrugs is limited due to hydrophilicity conferred by the promoiety, thus fully satisfying the requirements for a colon-specific prodrug (Jung et al., 2000, Jung et al., 2001).

Taurine, a free amino acid not incorporated into protein, protects tissues from the damage in a variety of models including IBD that share inflammation as a common pathogenic feature (Stapleton et al., 1997). In a previous report, we adopted taurine as a promoiety and synthesized 5-aminosalicyltaurine (5-ASA-Tau) as a colon-specific prodrug of 5-ASA, as expecting that taurine acts as not only a colon-specific promoiety but also a therapeutically active agent. The results from in vitro evaluation of the prodrug showed that it is cleaved into 5-ASA and taurine in the cecal contents while bio/chemically stable in the contents of the upper intestine (Jung et al., 2003). In this study, 5-ASA-Tau was in vivo-evaluated as a colon-specific prodrug for treatment of IBD using a TNBS-induced colitis model. Our data show that taurine conjugation of 5-ASA confers a limited systemic absorption and a greater efficiency of colonic delivery to 5-ASA, which is comparable to other amino acid-5-ASA conjugates. Furthermore, intracolonic treatment with combined taurine/5-ASA elicits an additive effect in healing 2,4,6-trinitrobenzene sulfonic acid-induced colitis rats and oral administration of 5-ASA-Tau is slightly more effective in ameliorating the colitis than that of sulfasalazine.