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The effect of dose on phenytoin pharmacokinetics was examined in the rat. In a randomized study on nine animals (not crossed over) it was observed that the apparent half-life ((t 1/2) of this drug increased four-fold as dose was increased from 10 to 50 mg/kg (6 1/2 - 64 +/- 42 min vs. 267 +/- 118 min, respectively; mean +/- S.D.). In a crossover study on three animals, an even larger dose-dependent increase in t 1/2 was observed (37.8 vs. 271 min). Finally, six animals received the 10 and 50 mg/kg doses in a randomized crossover fashion and urine was collected for 72 hours. A dose-dependent decrease in the fraction of the dose excreted as conjugates of 5-(p-hydroxyphenyl)-5-phenylhydantoin (59 +/- 20 vs. 39 +/- 12%) was found. It is concluded that phenytoin pharmacokinetics in the rat are non-linear but that a simple one compartment Michaelis-Menten model cannot account for the observed behavior.

The apparent steady state blood concentration of lidocaine in dogs depends on the animal's lidocaine treatment history. For example, an infusion of 50 microgram/Kg/min X 240 min followed immediately by an infusion of 125 microgram/Kg/min X 240 min yields steady state lidocaine levels which are consistent with a linear drug dispositional system. However, when the sequence of these infusions is reversed the apparent steady state level during the low infusion rate step is much greater than those predicted from the steady state level observed during the high infusion rate (assuming a linear dispositional model). These data suggest that high dose lidocaine infusion treatment alters the dog's ability to clear lidocaine during a subsequent low infusion rate treatment period.