Is phenytoin metabolism dose-dependent by enzyme saturation or by feedback inhibition?

The suggestion from animal experiments that phenytoin metabolism may be dose-dependent in man due to feedback inhibition by the major metabolite, 5-(p-hydroxyphenyl)-5-phenylhydantoin, was examined in 3 normal subjects by measuring phenytoin clearance during an intravenous infusion of the metabolite and during a control infusion of solvent. Clearance was measured using both carbon-labeled and unlabeled phenytoin. The infusion of metabolite did not produce any consistent change of phenytoin clearance, suggesting that feedback inhibition does not occur in man.