Drugdrug interactions and elevated free anticonvulsant concentrations

Sandyk (91) reported a case where phenytoin toxicity was induced by ibuprofen. This was due to displacement of phenytoin from protein binding by a strongly protein-bound drug ibuprofen. Tsanaclis et al. studied plasma protein binding of phenytoin in nine epileptic patients before and during addition of sodium valproate to the drug therapy. The mean Fu of phenytoin increased from a mean value of 13.5-18.2%. The total phenytoin concentrations were reduced. The authors concluded that valproic acid displaces phenytoin from plasma protein-binding sites but does not inhibit its metabolism (92). Pospisil and Perlik (93) demonstrated in vivo significant decreases in phenytoin protein binding because of the presence of valproic acid or primidone. Penicillins including oxacillin and dicloxacillin were effective in displacing phenytoin from its binding sites. In vivo, the total phenytoin concentration in serum decreased during penicillin administration while the free phenytoin concentrations increased (94). However, phenytoin-oxacillin interaction is not significant at a lower dose of oxacillin usually prescribed in oral therapy. However, the interaction is significant at higher oxacillin doses especially in patients with hypoalbuminemia (95). In vitro and in vivo displacement of phenytoin by antibiotics ceftriaxone, nafcillin, and sulfamethoxazole also have been reported (96). Strongly protein-bound drugs that may displace phenytoin from protein-binding sites are summarized in Table 5.

Several non-steroidal anti-inflammatory drugs such as salicylate, ibuprofen, tolmetin, naproxen, mefenamic acid, and fenoprofen can displace phenytoin, valproic acid, and carbamazepine from protein-binding sites (97). Blum et al. reported that tenidap sodium (an anti-inflammatory drug) 120 mg/day at steady state increased the percentage of protein binding of phenytoin in plasma by 25%. The authors concluded that because tenidap increases the percentage of unbound phenytoin in plasma, when monitoring plasma phenytoin concentration, free phenytoin concentrations also should

Table 5

Common Strongly Protein-Bound Drugs that Displace Phenytoin from Protein-Binding Sites and May Lead to a Higher Free Fraction

Drugs that May Displace Phenytoin from Protein Binding

Valproic acid











Mefenamic acid


Ceftriaxone be considered (98). Reduced interaction between phenytoin and valproic acid with non-steroidal anti-inflammatory drugs in uremia has been described. The reduced interactions may be due to the presence of inhibitors (97). Unexpected suppression of free phenytoin concentration by salicylate in uremic sera because of the presence of inhibitor had also been reported (99). Carbamazepine-salicylate and digitoxin-valproic acid interactions are also reduced in uremic sera because of the presence of inhibitors (100,101).

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