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