The Role of Sex, Age and Genetic Polymorphisms of CYP Enzymes on the
Pharmacokinetics of Anticholinergic Drugs
Abstract
Drugs exhibiting anticholinergic properties are commonly used by older
adults even with the associated risk of adverse drug events. Aging, sex
and genetic polymorphisms of cytochrome P450 (CYP) enzymes are
associated with alterations in pharmacokinetic processes which may
increase drug exposure and further increase the risk of adverse drug
events. Age-related changes include; pseudocapillarization of liver
sinusoidal endothelial cells which limit passage of drugs through the
liver, an approximate 3.5% decline in CYP450 content for each decade of
life, and a reduction in kidney function reducing drug excretion.
Sex-related differences include; women having delayed gastric and
colonic emptying, higher gastric pH, reduced catechol-O-methyl
transferase activity, reduced glucuronidation, and reduced renal
clearance and men having larger stomachs which may allow them to
dissolve and absorb medication more completely. The overlay of poor
metabolism phenotypes for CYP2D6 and CYP2C19 may further modify
anticholinergic drug exposure in a significant proportion of the
population. These factors help explain clinical trials that show older
adults and specifically women achieve higher plasma concentrations of
anticholinergic drugs. Despite this knowledge, age and sex are rarely
considered when making decisions about the dosing of anticholinergic
medications. As this is relevant to the future use of personalized
medicine, the objective of this review is to provide a clinical
perspective on age, sex, and CYP genetic polymorphisms and their role in
the metabolism and exposure to anticholinergic drugs. Future work needs
to account for age, sex and CYP polymorphism so that we may better
approach personalized medicine for optimal outcomes.