The debrisoquin hydroxylation phenotype does not predict the metabolism of phenytoin

Abstract

Phenytoin plasma elimination kinetics and accrual of phenytoin metabolites in urine were studied in seven rapid and five slow hydroxylators of debrisoquin. There was no interphenotypic difference in phenytoin clearance, plasma half-life, volume of distribution, maximum rate of metabolism (Vmax), or Michaelis-Menton constant (Km). The total recovery of metabolites as percentage of given dose and the metabolite profiles in urine were similar for the two debrisoquin hydroxylator phenotypes. Similarly, no differences were observed between the groups with respect to stereoselective production of either dihydrodiol or para-phenolic metabolites of phenytoin. The debrisoquin hydroxylation phenotype was also investigated in 74 epileptic patients treated with phenytoin. Vmax and Km were graphically estimated from plasma concentrations at varying phenytoin dosage regimens in 36 of the patients. There was no correlation between the debrisoquin hydroxylation index and Vmax or Km. We conclude that the debrisoquin hydroxylation phenotype has no predictive value in guiding phenytoin dosage.