Free Phenytoin Concentrations and Clinical Outcome

Soldin (39) reported that in his personal experience, free phenytoin is the most requested free drug level by clinicians. Phenytoin is 90% bound to serum proteins, mainly albumin. Phenytoin does not show any concentration-dependent binding within the therapeutic range. Kilpatrick et al. (53) reported that unbound phenytoin concentration (1.2-2.5 ^g/mL) reflected the clinical status of a patient equally or better than the total phenytoin concentration. Booker (4) earlier reported that free phenytoin concentration correlated better with toxicity, and the authors observed no toxicity at free phenytoin concentration of 1.5 ^g/mL or less. In patients with greatly decreased albumin levels, free phenytoin is the better indicator of effective plasma concentrations (therapeutic arrange: 0.8-2.1 ^g/mL) (54). Dutkiewicz et al. showed that in hyperc-holesterolemia and in mixed hyperlipidemia, the blood level of free phenytoin was elevated. The effect was probably related to displacement of phenytoin by free fatty acids (55,56). In eclampsia, free phenytoin levels are usually abnormally high although total phenytoin levels are within therapeutic range. Unfortunately, neither total nor free phenytoin levels are good predictors of seizure control (57). The binding of phenytoin to serum albumin can be altered significantly in uremia. The lower protein-binding capacity of phenytoin in uremia can be related to hypoalbuminemia, structural modification of albumin, and accumulation of uremic compound in blood that displaces phenytoin from protein-binding sites (58-60).

Monitoring free phenytoin concentration is very important in patients with hypoal-buminemia to avoid toxicity. Lindow et al. (61) described severe phenytoin toxicity associated with hypoalbuminemia in critically ill patients that was confirmed by direct measurement of free phenytoin. Zielmann et al. reported that in 76% of 38 trauma patients, the free phenytoin fraction was increased to as high as 24% compared with 10% Fu in otherwise healthy subjects. The major causes of elevated free phenytoin were hypoalbuminemia, uremia, and hepatic disease (62). The authors recommended monitoring of free phenytoin in such patients. Thakral et al. reported a case where a 19-year-old man who developed blurred vision and xanthopsia after administration of phenytoin for status epilepticus. The free phenytoin level was found to be toxic. Phenytoin was withheld, and the patient experienced partial recovery. The authors concluded that phenytoin toxicity as revealed by an elevated free phenytoin concentration contributed to this acute visual dysfunction (63). Burt et al. studied total and free phenytoin levels in 139 patients. Free phenytoin concentrations were 6.8-35.3% of total phenytoin concentrations (expected range 8-12%). Clinical indications responsible for variations were hypoalbuminemia, drug interactions, uremia, pregnancy, and age. The authors concluded that monitoring total phenytoin is not as reliable as free phenytoin as a clinical indicator for therapeutic concentrations and recommended that therapeutic monitoring of phenytoin should be only the free concentration (64). Recently, Iwamoto et al. (65) also reiterated the need of free phenytoin monitoring in patients receiving phenytoin monotherapy because free phenytoin fraction was significantly influenced by aging, mean creatinine clearance, and serum albumin levels in the patient population they studied. Deleu (66) recommended a dose of 6.1 mg/kg to achieve a free phenytoin concentration of 1.5 ^g/mL.

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