The effects of phenytoin dosage on the induction of alpha 1-acid glycoprotein and antipyrine clearance in the dog.

Doses of phenytoin from 90 to 800 mg/d were used to study induction of hepatic cytochrome P-450 and plasma alpha 1-acid glycoprotein in dogs. The antipyrine clearance was increased by 80%, which is equivalent to an increase in cytochrome P-450 of 140%, and the plasma glycoprotein concentration rose 200% at the highest dose of phenytoin used. Plasma concentrations of phenytoin were measured at each dose level to provide a definitive value for the amount of inducer present. These data were used to assess the concentration-response relationship for phenytoin inducing either cytochrome P-450 or the glycoprotein. A simple relationship between concentration and effect was not observed, suggesting a complex mechanism of induction.