The Relationship between Phenazone (Antipyrine) Metabolite Formation and Theophylline Metabolism in Healthy and Frail Elderly Women

Abstract

The influence of aging on the metabolism of phenazone (antipyrine), and the relationship between the formation of 3 phenazone metabolites and the metabolic clearance of theophylline in healthy and frail elderly women, were examined. Whereas the elimination half-life did not change, clearance of phenazone decreased by about 50% with age in healthy women receiving phenazone without theophylline. However, the summation of the urinary recovery of phenazone and the measured metabolites, expressed as percentage of the phenazone dose, was lower in the healthy elderly (37 +/- 9% vs 74 +/- 15%). In both healthy and frail females the clearance of formation of 4-hydroxy-phenazone and the metabolic clearance of theophylline correlated strongly (r = 0.93 and 0.90, respectively). In non-healthy elderly females, strong correlations were also observed between the other metabolic pathways of phenazone and the metabolic clearance of theophylline. Coadministration of theophylline in the elderly increased the percentage of the phenazone dose excreted as the measured metabolites. A considerably higher interindividual variability in the disposition of phenazone and theophylline was observed in the frail elderly women. This high degree of variability in drug metabolism may be one of the explanations for the problems often occurring after drug prescription in the elderly.

p16INK4a, a Senescence Marker, Influences Tenofovir/Emtricitabine Metabolite Disposition in HIV‐Infected Subjects

“…Although earlier PK work demonstrated a link between frailty and drug clearance,18, 19, 20, 21, 22 our model did not indicate that such a relationship exists for these drugs or their metabolites. We did recruit low numbers of frail participants in this study, likely due to selection bias, rather than lack of frail patients in the clinics used for recruitment, as study participation required separate visits to the research center outside of clinical care.…”

“…Although not fully validated in HIV‐infected patients, links to development of the phenotype and increased morbidity and mortality in HIV‐infected patients have been shown 16, 17. In older literature, frailty has primarily been cited as the cause of age‐related altered drug CL not due to well‐established changes in kidney function that decrease CL of renally eliminated drugs 18, 19, 20, 21, 22. On a cellular level, the tumor suppressor gene p16 INK4a is a marker of senescence and its expression in peripheral blood T‐cells has been shown to be a biomarker of aging 23.…”

“…16,17 In older literature, frailty has primarily been cited as the cause of age-related altered drug CL not due to well-established changes in kidney function that decrease CL of renally eliminated drugs. [18][19][20][21][22] On a cellular level, the tumor suppressor gene p16 INK4a is a marker of senescence and its expression in peripheral blood T-cells has been shown to be a biomarker of aging. 23 As chronologic age alone does not capture either of these phenomena, the goal of this investigation was to quantify markers of biologic aging in HIV-infected participants along the age spectrum receiving TDF/FTC, and use nonlinear mixed effects modeling to test the hypothesis that frailty and cellular senescence decrease the CL of TFV/FTC and their metabolites.…”

Drug metabolism and ageing

“…Similar findings have been reported with metoclopramide [41] not seen in the fit elderly and additional decrements in acetanilide clearance [42]. Furthermore, increased variability in frail elderly compared with 'fit' elderly women has been demonstrated for theophylline clearance [43]. More recent studies of benzoyl, butyryl, and acetylcholinesterases have also demonstrated no decline in vivo with age [44].…”

Population Pharmacokinetics Modeling of Unbound Efavirenz, Atazanavir, and Ritonavir in HIV‐Infected Subjects With Aging Biomarkers

“…A characteristic phenotype has been described20 and applied to the HIV population, which demonstrates occurrence of this phenotype at ages 10 years younger than uninfected controls 21. Significant decreases in drug clearance of 50% or greater have been demonstrated in the frail HIV‐negative elderly for acetaminophen,22 metoclopramide,23 and antipyrine24 compared with younger, healthier, HIV‐negative subjects. This increase in exposure is likely due to a combination of decreased renal clearance and cytokine‐induced downregulation of metabolic enzymes 25…”