Evaluation of 5-aminosalicyltaurine as a colon-specific prodrug of 5-aminosalicylic acid for treatment of experimental colitis
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.
Section snippets
Drugs, chemicals and animals
5-Aminosalicylic acid was purchased from Tokyo Kasei Kogyo Co. (Tokyo, Japan). Sulfasalazine and 2,4,6-trinitrobenzene sulfonic acid (TNBS) were purchased from Sigma Chemical Co. Inc. (St. Louis, MO, USA). All other chemicals were reagent-grade, commercially available products. Male Sprague–Dawley rats (240–260 g, 8 weeks old) were purchased from Daehan Biotec Co. Ltd. (Daegu, Korea) and housed in the animal care facility at Pusan National University, Busan, Korea. 5-Aminosalicyltaurine,
Taurine conjugation of 5-ASA limits the systemic absorption of 5-ASA
5-Aminisalicylic acid is reportedly absorbed rapidly via a carrier-mediated or/and paracellular transport in the upper intestine. To examine whether taurine conjugation of 5-ASA negatively affected the transports of 5-ASA, thus limiting its systemic absorption, either 5-aminosalicyltaurine or 5-ASA was administered orally to rats and plasma concentration profiles of 5-ASA-Tau and 5-ASA (5-ASA + N-acetyl-5-ASA) were determined and compared. As shown in Fig. 1A, while oral administration of 5-ASA
Discussion
In this report, we in vivo-evaluated 5-ASA-Tau as a colon-specific prodrug of 5-ASA for treatment of IBD. Our data demonstrate that taurine conjugation of 5-ASA greatly reduced systemic absorption of 5-ASA and effectively delivered 5-ASA to the large intestine. Furthermore, taurine (promoiety) released from 5-ASA-Tau potentiated the ability of 5-ASA (active ingredient) to ameliorate TNBS-induced colitis rat, and 5-ASA-Tau was slightly more effective than sulfasalazine in alleviating the colonic
Acknowledgement
This work was supported by grant No. RO4-2003-000-10151-0 from the Korea Science and Engineering Foundation.
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