EFFECTS OF UREMIC TOXINS AND FATTY-ACIDS ON SERUM-PROTEIN BINDING OF FUROSEMIDE - POSSIBLE MECHANISM OF THE BINDING DEFECT IN UREMIA

To elucidate the mechanism of impaired serum binding of furosemide obs erved in patients with renal dysfunction, we examined in vitro the ser um protein binding of furosemide the absence and presence of uremic to xins that are endogenously retained solutes in uremic serum and act as inhibitors of drug binding. Analysis of the binding data of furosemid e at its therapeutic concentration (6.6 mg/L) indicated that, among th e four uremic toxins studied, 3-carboxy-4-methyl-5-propyl-2-furanpropi onate (CMPF) showed the greatest inhibitory potency for the binding of furosemide to serum; moveover, the inhibition was competitive. CMPF t hus most likely represents the primary determinant for the serum bindi ng defect of furosemide in uremia. However, CMPF and oleate appear to exert a synergistic effect on the inhibition of furosemide serum bindi ng-perhaps through a cascade effect on furosemide-binding inhibition i n the oleate-CMPF-furosemide system, in which the binding of oleate to its low-affinity sites indirectly displaces furosemide from albumin a nd thus increases the transiently liberated CMPF molecules. Similar ca scade effects on furosemide binding in the presence of CMPF were also originated by other long-chain (C-18) fatty acids, linoleate and stear ate, although to a lesser extent. Because CMPF is not effectively remo ved by ordinary hemodialysis treatment, the combined direct and cascad e effects of CMPF and fatty acids appear to contribute to the increase in the free fraction of furosemide during hemodialysis.