Relationship between mephenytoin oxidation polymorphism and phenytoin, methylphenytoin and phenobarbitone hydroxylation assessed in a phenotyped panel of healthy subjects.
1. In a phenotyped panel of healthy subjects correlations were studied between the oxidation of mephenytoin, phenytoin, methylphenytoin and phenobarbitone, with respect to the formation of their 4-hydroxy metabolites (OH-). 2. On different occasions phenotyped extensive metabolizers (EM; n = 16) and poor metabolizers (PM; n = 4) of mephenytoin received phenytoin (100 mg), methylphenytoin (100 mg) and phenobarbitone (50 mg) and urine was collected up to 24 h. The excreted 4-hydroxy metabolites of all compounds were measured by h.p.l.c. 3. Urinary recovery of OH-phenytoin was 31.0 +/- 11.7%, of OH-methylphenytoin 3.4 +/- 2.7% and of OH-phenobarbitone 1.4 +/- 1.2%. No correlation was found between the recovery of OH-mephenytoin and OH-phenytoin. A subject who produced virtually no OH-phenytoin was an EM of mephenytoin, confirming a dissociation of mephenytoin polymorphism and phenytoin hydroxylation. 4. The correlation coefficient for OH-mephenytoin and OH-methylphenytoin recovery was 0.71 (Spearman rank, P = 0.002). The PMs of mephenytoin excreted the least amount of OH-methylphenytoin, suggesting a cosegregation of the 4-hydroxylation pathways. No correlation was found between the urinary recovery of OH-phenobarbitone and that of the other 4-hydroxy metabolites.
Schellens
J H
JH
Divison of Pharmacology, University of Leiden, The Netherlands.
van der Wart
J H
JH
Breimer
D D
DD
D000328:Adult; D005260:Female; D006801:Humans; D006827:Hydantoins / Q000378:metabolism*; D006900:Hydroxylation; D008297:Male; D008617:Mephenytoin / Q000378:metabolism*; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000378:metabolism*; D010641:Phenotype; D010672:Phenytoin / Q000378:metabolism*
D006827:Hydantoins; D010672:Phenytoin; D008617:Mephenytoin; D010634:Phenobarbital