Phenytoin: The pseudosteady-state phenomenon

Abstract

After reaching an apparent steady state, plasma phenytoin (PHT) levels may then undergo inexplicable changes, a phenomenon called " pseudosteady state". We evaluated 13 pseudosteady -state periods in 10 inpatients with complex partial seizures. Eleven of the periods occurred after a change in PHT dosage and two after drug withdrawal. The pseudosteady -state period began 2 to 12 days (means = 5.7 days) after dosage change and lasted 5 to 10 days (means = 6.3 days), during which plasma PHT levels were stable (+/- 5%). Plasma PHT levels thereafter fluctuated spontaneously by greater than 25% for 5 to 22 days (means = 10.8 days). A final steady-state level was reached 13 to 31 days (means = 21.4 days) after the first dosage change. Falling plasma PHT levels increased seizure frequency in two patients, and a level of 52 micrograms/ml led to medication toxicity in another.

The clinical value of free phenytoin levels

“…Evidence that PHT kinetics may fit a multicompartment model [23) also implies that binding changes may not have a clinically significant effect on drug distribution [b]. Monks and Richens {l6} suggested that rapid diffusion of free PHT into a moderately large volume of distribution and increased hepatic metabolism of unbound drug would minimize plasma level fluctuations resulting from binding variability.…”

“…Theoretical considerations suggest that distribution of PHT, with a low drug-protein complex association constant, may be less affected by protein binding than by the ability to penetrate the blood-brain barrier, tissue solubility and binding, and mechanisms of metabolism and excretion [9, 13,221. Evidence that PHT kinetics may fit a multicompartment model [23) also implies that binding changes may not have a clinically significant effect on drug distribution [b]. Monks and Richens {l6} suggested that rapid diffusion of free PHT into a moderately large volume of distribution and increased hepatic metabolism of unbound drug would minimize plasma level fluctuations resulting from binding variability.…”

Effects of Antiepileptics on Nutritional Status

“…The literature of the mid-1980s applied the term "pseudo-steady-state" to phenytoin pharmacokinetics ( 50 ). This term implied that a person was at steady-state or equilibrium with phenytoin, but in reality was not.…”