The role of sex, age and genetic polymorphisms of CYP enzymes on the pharmacokinetics of anticholinergic drugs

There is evidence that use of drugs with anticholinergic properties increases the risk of cognitive impairment, and increased exposure to these drugs potentiates this risk. Anticholinergic drugs are commonly used even with associated risk of adverse events. Aging, sex, and genetic polymorphisms of cytochrome P450 (CYP) enzymes are associated with alterations in pharmacokinetic processes, which increase drug exposure and may further increase the risk of adverse drug events. Due to the increasing burden of cognitive impairment in our aging population and the future of personalized medicine, the objective of this review was to provide a critical clinical perspective on age, sex, and CYP genetic polymorphisms and their role in the metabolism and exposure to anticholinergic drugs. Age-related changes that may increase anticholinergic drug exposure include pseudocapillarization of liver sinusoidal endothelial cells, an approximate 3.5% decline in CYP content for each decade of life, and a reduction in kidney function. Sex-related differences that may be influenced by anticholinergic drug exposure 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 affect medication absorption. 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 findings of clinical trials that show older adults and specifically older women achieve higher plasma concentrations of anticholinergic drugs and that poor metabolizers of CYP2D6 experience increased drug exposure. Despite this knowledge neither age, sex nor CYP phenotype are routinely considered when making decisions about the use or dosing of anticholinergic medications. Future study of anticholinergic medication needs to account for age, sex and CYP polymorphisms so that we may better approach personalized medicine for optimal outcomes and avoidance of medication-related cognitive impairment.