FREQUENCY-DISTRIBUTION OF DAPSONE N-HYDROXYLASE, A PUTATIVE PROBE FORP4503A4 ACTIVITY, IN A WHITE-POPULATION

Phenotypic trait values in 166 healthy white subjects (age range, 18 t o 88 years) were determined for dapsone N-hydroxylation, dapsone N-ace tylation, debrisoquin 4-hydroxylation, and S-mephenytoin 4'-hydroxylat ion after single oral dose administration of the probe drugs dapsone ( 100 mg), debrisoquin (10 mg), and mephenytoin (100 mg). No association s or evidence of cosegregation were found between the individual route s of metabolism. Dapsone N-hydroxylation exhibited a unimodal distribu tion, with marked (tenfold) intersubject variability, and aging was as sociated with reduced N-oxidation. However, the other measured routes of metabolism were age independent, but intersubject variability in al l of the trait measurements increased with age. In subjects younger th an 50 years, S-mephenytoin 4'-hydroxylation was modestly (34%) less in men than in women. In contrast, dapsone N-acetylation, dapsone N-hydr oxylation, and debrisoquin 4-hydroxylation were not influenced by gend er. Previous smoking habit and alcohol consumption were not associated with a difference in any of the four routes of metabolism. Accordingl y, the measured phenotypic traits of drug oxidation and N-acetylation appear to be quite robust in regard to some common demographic variabi lities present in population studies, with the exception of dapsone N- hydroxylase, which is affected by aging.