Absence of correlations among three putative in vivo probes of human cytochrome P4503A activity in young healthy men.
In vitro studies with human liver microsomes have shown that erythromycin N-demethylation, dapsone N-hydroxylation, and the 6 beta-hydroxylation of cortisol are all primarily mediated by P4503A4. Trait measurements to assess the in vivo level of activity of these separate oxidations have also been developed previously. This study investigated the relationships among the three phenotypic trait measurements in 30 young healthy white men. The frequency distributions of the trait values were all unimodal, with a twofold range for the erythromycin breath test and the urinary dapsone recovery ratio; the urinary 6 beta-hydroxycortisol/cortisol ratio was more variable, with a 17-fold range of values. No statistically significant correlations were observed among any of the trait measurements (dapsone recovery ratio versus erythromycin breath test: r = -0.07, p = 0.7; urinary 6 beta-hydroxycortisol/cortisol ratio versus erythromycin breath test: r = -0.12, p = 0.6; urinary 6 beta-hydroxycortisol/cortisol ratio versus dapsone recovery ratio: r = 0.13, p = 0.5. This lack of any relationship was unexpected and the reason(s) is unknown; however, it is possible that factors such as route of administration and extrahepatic metabolism in the intestinal epithelium and kidney are involved. Further studies are required to identify and validate the use of an appropriate in vivo probe of P4503A4 in humans.
Kinirons
M T
MT
Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602.
O'Shea
D
D
Downing
T E
TE
Fitzwilliam
A T
AT
Joellenbeck
L
L
Groopman
J D
JD
Wilkinson
G R
GR
Wood
A J
AJ
D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases; D001944:Breath Tests; D002245:Carbon Dioxide / Q000032:analysis; D002250:Carbon Radioisotopes; D002623:Chemistry Techniques, Analytical / Q000379:methods; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003622:Dapsone / Q000652:urine; D004917:Erythromycin / Q000032:analysis / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000378:metabolism / Q000652:urine; D006900:Hydroxylation; D008297:Male; D008745:Methylation; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D010641:Phenotype
D002250:Carbon Radioisotopes; D002245:Carbon Dioxide; C001380:6 beta-hydroxycortisol; D004917:Erythromycin; D003622:Dapsone; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D006854:Hydrocortisone