The development of Brequinar as an immunosuppressive drug for transplantation.

The preclinical and clinical characterization of Brequinar sodium has demonstrated the potential for the use of this drug as a component of a polytherapeutic treatment strategy to prevent the rejection of organ grafts. Brequinar, along with several other new immunosuppressive drugs, including Mizorbine, 15-deoxyspergualin, and Mycophenolate mofetil, is an antimetabolite with immunosuppressive activity and toxic side effects that are distinctly different from those of CsA and the newly characterized FK 506. This combination of effective antiproliferative activity exhibited by these newer agents and the well-established effect of CsA on T-lymphocyte activation offers the potential for the development of immunosuppressive regimens that are significantly more effective with fewer side effects for the patient. The concept of synergistic interaction between these two classes of immunosuppressive agents has been tested experimentally and found to be extremely effective for both allograft and xenograft models of graft rejection (Cosenza et al. 1993, 1993a, Stepkowski & Kahan 1993). It remains to be established that a similar synergism will exist for clinical transplantation. The effectiveness of CsA as a primary immunosuppressive agent, however, assures the inclusion of CsA in any polytherapeutic approach to be tested in the near future. New clinical trials designed to prove efficacy for immunosuppressive agents, such as BQR, will use CsA or FK 506 as a primary component of the treatment protocol. The combination of immunosuppressive agents that will eventually be applied in wide clinical use is not clear. While some new immunosuppressive agents have been more extensively tested clinically, BQR exhibits a number of unique features that make this compound particularly attractive for inclusion in new immunosuppressive regimens. The drug is readily soluble in aqueous solutions and can be administered intravenously or orally with equal effectiveness. Brequinar exhibits a high level of bioavailability following oral administration and an extended half-life that permits less frequent administration. While the metabolic byproducts of BQR have not been clearly described, there is good evidence that the parent compound exhibits the majority, if not all, of the immunosuppressive activity. The ability to monitor the parent drug directly or measure the depletion of enzyme products that reflect the activity of the drug are important features of the drug that simplify its use in a clinical setting. Although BQR exhibits important adverse side effects at high doses, the effects of the drug are characteristic of antimetabolites and are therefore predictable, constant, and reversible.(ABSTRACT TRUNCATED AT 400 WORDS)