Dose-dependence of the apparent half-life of phenytoin in the rat.
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.
D000758:Anesthesia; D000818:Animals; D001711:Biotransformation; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D007700:Kinetics; D010424:Pentobarbital; D010622:Phencyclidine; D010672:Phenytoin / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats
D010672:Phenytoin; D010424:Pentobarbital; D010622:Phencyclidine