S15176 and S16950 interaction with Cyclosporin A antiproliferative effect on cultured human lymphocytes
Cyclosporin A (CSA) is a uniquely potent immunosuppressant used world-wide to sustain organ transplantation. It has also been proven effective in a variety of autoimmune and related disorders. However, dose-dependent side-effects, particularly at the level of the kidney, may ultimately define the limits of clinical utility of the drug because they frequently mandate modification of therapy to avoid chronic renal insufficiency. The first site of nephrotoxicity is vasoconstriction at the efferent and afferent glomerular arterioles. The second site is cellular hypoxia. Both effects may add to impair renal function, but cellular ischemia occurs independently from vasoconstriction as cellular ischemia can be reproduced in vitro in renal cells as well as in isolated mitochondria of these renal cells. A major effect of CSA is to promote calcium accumulation in the mitochondrial matrix. This, in turn, diminishes ATP synthesis in a dose-dependent fashion. A variety of pharmacological attempts have been made to abrogate, or at least limit, CSA nephrotoxicity (for a review see). They have included vasodilators and anti-ischemics. Among anti-ischemics, trimetazidine might be a good choice, because it has been shown to prevent isolated mitochondria of rat kidney cells from the loss of ATP synthesis induced by CSA. In addition, trimetazidine minimized the functional alterations experimentally observed in rat liver submitted to a normothermic ischemia/reperfusion model performed without CSA. It was also shown that trimetazidine reverses the deleterious effects of ischemia-reperfusion in the isolated perfused pig kidney model. This cellular protective effect is due to the fact that a high level of trimetazidine is able to maintain mitochondrial homeostasis, particularly mitochondrial ATP synthesis. However, as this effect is only partial, more effective trimetazidine derivatives have been synthesized. Two of these, S-15176 and S-16950 were shown to be 5 times and 10 times (Morin et al., personal communication) respectively, more potent than the parent drug on the perfused rat liver model of ischemia/reperfusion; and were also capable of reversing the loss of ATP synthesis observed in isolated mitochondria exposed to CSA. However, they did not seem to act by the same mechanism, as under the same experimental conditions S-15176 counteracted the opening of the mitochondrial giant pore induced by a calcium overload, whereas S-16950 did not interfere with this permeability site of the mitochondrial membrane. (Jullien et al., personal communication). Every compound thus appeared as a potential candidate to a therapeutic association with CSA, provided that none of them decreased the immunosuppressive activity of CSA. Investigating this point has been the main objective of the present study. We have also looked for whether the effect of S-15176 on the homeostasis of mitochondrial Ca++, which is similar to that of CSA, might enhance the immunosuppressive effect of the latter.
Filed under: Pharmacokinetics