Experiences With Leflunomide in Solid Organ Transplantation

Abstract

Leflunomide seems to possess substantial immune suppressive potency in renal and liver transplant recipients and may be safely dosed for more than 300 days. The data suggest that calcineurin phosphatase inhibitors and prednisone can be safely reduced in patients with serum levels of active drug above 50 microg/mL. Because of a wide inter-patient range of active metabolite terminal half-life (>300%), monitoring of serum levels would seem to be an important part of its evaluation.

Polyoma BK virus-associated nephropathy in kidney-transplant patients: Effects of leflunomide on T-cell functions and disease outcome

“…Indeed, it has been previously shown that the addition of uridine to rat blood at the same time as malononitrilamides antagonizes the inhibitory effects of the drugs on lymphocyte proliferation and CD25 expression [39]. The persisting immunosuppression observed in our patients in whom MMF was replaced by leflunomide is in line with previous reports that found FK 778 to be efficient in preventing acute rejection after solid-organ transplantation [12,13].…”

“…It inhibits dihydroorotic acid dehydrogenase (DHOH), a mitochondrial enzyme necessary for orotate synthesis in the de novo pathway to uridine, and the inhibition of selected tyrosine kinases [10,11]. In solid organ-transplant patients, leflunomide has been shown to have a significant immunosuppressive effect, preventing and even reversing acute rejection [12,13]. In contrast, in in vitro culture systems, leflunomide has been shown to inhibit both cytomegalovirus and BKV replication [14][15][16].…”

Protective effects of leflunomide against ischemia-reperfusion injury of the rat liver

“…Leflunomide, an isoxazole derivative and a unique immunomodulatory and anti-inflammatory agent, is capable of treating rheumatoid arthritis, allograft and xenograft rejection, systemic lupus erythematosus, Crohn's disease, and prostate cancer [13][14][15][16][17]. Leflunomide is a prodrug that is rapidly converted in the gastrointestinal tract and plasma to its active, open ring metabolite, the malononitrilamide, A 771726 (2-cyano-3-hydroxy-N-(4-trifluoromethylphenyl) butenamide) [18].…”

The active metabolite of leflunomide, A77 1726, increases proliferation of human synovial fibroblasts in presence of IL-1β and TNF-α

“…1A), according to their known mitogenic effect on these cells. A77 1726 inhibited both the baseline MTS activity and the activity stimulated by cytokines when added at a final concentration of 100 µM, which is in the range of plasma concentrations in humans at a steady-state under daily doses of 20 mg [4,[22][23][24]. We then performed cell counts to examine whether this decrease in MTS activity was accompanied by a decrease in cell number.…”