Frequency distribution of dapsone N-hydroxylase, a putative probe for P4503A4 activity, in a white population.
Phenotypic trait values in 166 healthy white subjects (age range, 18 to 88 years) were determined for dapsone N-hydroxylation, dapsone N-acetylation, debrisoquin 4-hydroxylation, and S-mephenytoin 4'-hydroxylation after single oral dose administration of the probe drugs dapsone (100 mg), debrisoquin (10 mg), and mephenytoin (100 mg). No associations or evidence of cosegregation were found between the individual routes of metabolism. Dapsone N-hydroxylation exhibited a unimodal distribution, with marked (tenfold) intersubject variability, and aging was associated with reduced N-oxidation. However, the other measured routes of metabolism were age independent, but intersubject variability in all of the trait measurements increased with age. In subjects younger than 50 years, S-mephenytoin 4'-hydroxylation was modestly (34%) less in men than in women. In contrast, dapsone N-acetylation, dapsone N-hydroxylation, and debrisoquin 4-hydroxylation were not influenced by gender. Previous smoking habit and alcohol consumption were not associated with a difference in any of the four routes of metabolism. Accordingly, the measured phenotypic traits of drug oxidation and N-acetylation appear to be quite robust in regard to some common demographic variabilities present in population studies, with the exception of dapsone N-hydroxylase, which is affected by aging.
May
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DG
Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.
Porter
J
J
Wilkinson
G R
GR
Branch
R A
RA
D000107:Acetylation; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003622:Dapsone / Q000378:metabolism*; D003647:Debrisoquin / Q000378:metabolism; D005260:Female; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008617:Mephenytoin / Q000378:metabolism; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010641:Phenotype; D012044:Regression Analysis; D044465:White People / Q000235:genetics
D003622:Dapsone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D008617:Mephenytoin; D003647:Debrisoquin