Hepatic cytochrome P-4503A (CYP3A) activity in the elderly.
Elderly patients exhibit decreased clearance of multiple drugs biotransformed by the hepatic cytochromes P-450. The cytochromes P-450 are a superfamily of enzymes, which comprise a central component of phase I drug metabolism. Distinct isoforms metabolize specific drugs. In human liver microsomes, the glucocorticoid-inducible cytochrome P-450IIIA, CYP3A, catalyzes the N-demethylation of erythromycin. To examine the activity of hepatic CYP3A in elderly males and females, erythromycin N-demethylation was examined, as reflected by the recently described [14C]erythromycin breath test in 24 healthy volunteers, age 70-88. The [14C]erythromycin breath test was measured in normal elderly males and females to: (a) determine persistence of the gender-related dimorphism (evident in younger subjects) of CYP3A activity in the elderly population, (b) examine the effect of % ideal body weight, age, diet, and medication use on the activity of human hepatic CYP3A, and (c) compare breath test results obtained in normal geriatric volunteers with published results obtained in younger subjects, to determine aging-related alterations in CYP3A enzyme activity. Erythromycin N-demethylation varied fivefold among these patients. Similar to earlier studies examining erythromycin N-demethylation in younger subjects, CYP3A activity was found to vary with gender in the geriatric cohort. [14C]Erythromycin N-demethylation at 60 min was 3.14% +/- 0.75 (n = 13) in females and 2.15% +/- 0.77 (n = 11) in males (P = 0.005). In evaluating the role of % ideal body weight and % dietary fat using multivariable linear regression analyses, [14C]erythromycin N-demethylation, was found to decline significantly as % ideal body weight increased (P = 0.001). This was not confounded by gender. [14C]Erythromycin N-demethylation was not related to dietary fat intake (P less than 0.13). [14C]Erythromycin N-demethylation in the elderly volunteers was similar to values reported for subjects aged 20-60. Performance of a new non-invasive test of the human hepatic glucocorticoid-inducible CYP3A in a geriatric cohort suggests that: (a) the gender-related heterogeneity in function of the glucocorticoid inducible human CYP3A persists during normal aging, (b) that the activity of CYP3A may decrease in obesity, and (c) that the activity of CYP3A is stable throughout normal ageing.
Hunt
C M
CM
Department of Medicine, Duke University Medical Center, Durham, NC 27710.
Westerkam
W R
WR
Stave
G M
GM
Wilson
J A
JA
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004032:Diet; D004917:Erythromycin / Q000378:metabolism; D005260:Female; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008297:Male; D009765:Obesity / Q000201:enzymology; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D012727:Sex Characteristics; D013379:Substrate Specificity
D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating