Influence of DH/DL alleles regulating debrisoquine oxidation on phenytoin hydroxylation

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Abstract
Eleven subjects of previously determined debrisoquine oxidation phenotype status (extensive metabolizer [EM], n = 5; poor metabolizer [PM], n = 6) were studied for their ability to perform the aromatic 4-hydroxylation of the anticonvulsant phenytoin. The PM subjects studied were slower metabolizers of phenytoin than EM subjects in terms of the metabolite formation rate constant (kfHPPH: EM, 0.030 .+-. 0.007/h; PM, 0.016 .+-. 0.003/h, 2 P < 0.001) and cumulative excretion of 4-hydroxyphenytoin (48 h after dosing: EM, 52.8 .+-. 10.7%; PM, 36.9 .+-. 7.0%, 2P < 0.01). The metabolic oxidation of phenytoin is influenced by the same DH and DL alleles, acting at the same locus, that regulate the hydroxylation of debrisoquine and impaired metabolism of phenytoin may be expected to occur in .apprx. 9% of the population, being transmitted as an autosomal-recessive trait. Debrisoquine oxidation phenotyping may have predictive value in guiding phenytoin dosage, particularly in those with impaired oxidation.

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