Practical and theoretical aspects of phenytoin administration. I. Relationship between dose and plasma concentration

In 28 patients the dose-plasma concentration relationship of phenytoin was studied by stepwise varying of the dose of phenytoin and observing the effect on the plasma concentration after an equilibration period of 4 weeks. Plasma concentrations were determined by two laboratories independently. Comedication (only phenobarbital) was fixed. It appeared that after nonconsecutive 4-week equilibration periods, equal doses could yield substantially different plasma concentrations. It is suggested that an equilibration period of at lest 4 weeks must be observed between a dose decrement in the high dose range and a check of the resulting steady state plasma concentration. The slow decrement of phenytoin plasma concentration after decreasing the dose cannot be explained by the Michaelis-Menten concept. In this study the maximum safe dose for never exceeding a phenytoin plasma concentration of 15 microgram/ml ws 200 mg/24 h. For phenobarbital a ratio of about 1:10 or more between dose (in mg/kg/24 h) and plasma concentration (in microgram/ml) was nearly always observed in 27 of 28 patients.