Effect of age on the metabolism and transport of anticholinergic
medications
In humans, it is well established that total hepatic CYP enzyme levels
decline from about age 40 onwards. This has been quantified as about a
3.5% decline in CYP enzyme content for each decade of life potentially
influencing the elimination of anticholinergic drugs undergoing
metabolism by the CYP enzyme system, resulting in greater exposure to
the pharmacologic properties of these agents52,103. An
older study investigating the metabolic ability of CYP 450 enzymes in
aging revealed that CYP3A4 was reduced in older adults. The microsomal
content of CYP3A4 was found to decrease by approximately 8% per decade
of life52. This trial failed to show a difference in
CYP1A2, or CYP2C based on aging. An in vitro study of healthy human
liver samples obtained during surgical procedures from 43 subjects
between the ages of 27 and 83 showed no variation in CYP3A4 activity in
relation to age. In this study, CYP3A4 activity was quantified by
measuring erythromycin N-demethylation. While erythromycin
N-demethylation has been shown to decline with age, the results of this
study suggests that the age-related decline in enzyme activity is not
due to declining CYP3A4 activity. Rather, other patient factors such as
renal blood flow, renal filtration or body composition are likely
contributing54. In females intestinal CYP3A4 content
has been shown to decrease by approximately 20% after
menopause43 which may reduce intestinal CYP3A4
metabolism and contribute to an age-dependent difference in CYP3A4
metabolism. Possibly due to a lack of studies, this decrease in
intestinal CYP3A4 in postmenopausal women has not been shown to be
clinically meaningful to date. Decreases in the clearance of CYP3A4
substrate drugs suggest that older people may experience increased
adverse effects due to reduction in clearance of drugs that rely on
CYP3A4 for metabolism prior to elimination104.
Drug Conjugation has been shown in several studies as remaining fairly
constant with respect to age105. Undeniably, numerous
factors such as genetics, medication use and
frailty106,107 can influence glucuronidation and
sulfonation but in younger and older healthy people glucuronidation and
sulfonation are not statistically significantly different. In aging rat
models, liver sinusoidal endothelial cells undergo
pseudocapillarization108,109 a process characterized
by loss of sinusoidal fenestrations, thickening of the endothelium,
perisinusoidal collagen deposition and basal lamina
formation110. This process suggests that drug passages
through the liver are reduced in size which in theory could prevent
large molecules, in particular protein therapeutics and extensively
protein bound drugs, from travelling through the liver and being
cleared; this has been shown for liposomal doxorubicin in agedvs. young rats111. The relevance of these
changes to anticholinergic drug pharmacokinetics remains to be
determined