DISPLACEMENT OF VALPROIC ACID AND CARBAMAZEPINE FROM PROTEIN-BINDING IN NORMAL AND UREMIC SERA BY TOLMETIN, IBUPROFEN, AND NAPROXEN - PRESENCE OF INHIBITOR IN UREMIC SERUM THAT BLOCKS VALPROIC ACID-NAPROXEN INTERACTIONS

Displacement of valproic acid (90-95% bound to albumin) and carbamazep ine (80% bound to albumin) by salicylate, leading to higher concentrat ions of pharmacologically active free drugs, has been reported. We stu died the possibility of displacement of valproic acid and carbamazepin e by other strongly albumin-bound nonsteroidal antiinflammatory drugs tolmetin, ibuprofen, and naproxen. We observed statistically significa nt displacement of carbamazepine from protein binding in uremic serum at higher therapeutic concentrations of all three antiinflammatory dru gs we studied, whereas in normal serum, we observed statistically sign ificant displacement only with 75 mu g/ml of naproxen. For valproic ac id, we observed significant displacement even at lower therapeutic con centrations with all three drugs when the study was conducted using a normal serum pool. In the uremic serum pool, we observed significant d isplacements only with tolmetin and ibuprofen, whereas we observed no significant displacement of valproic acid even with higher concentrati ons of naproxen. We conclude that tolmetin, naproxen, and ibuprofen ca n displace both carbamazepine and valproic acid from protein binding, but uremic serum contains an inhibitor that blocks valproic acid-napro xen interaction.