Polypharmacy Results in Functional Impairment in Mice: Novel Insights into Age and Sex Interactions.

Males and females may respond differently to medications, yet knowledge about sexual dimorphisms in the effects of polypharmacy remains limited, particularly in aging. This study aimed to assess the effect of high Drug Burden Index (DBI) polypharmacy treatment compared to control on physical function and behavior in young and old, male and female mice. We studied whether age and sex play a role in physical function and behavior following polypharmacy treatment, and whether they are parallelled by differences in serum drug levels. Young (2.5 months) and old (21.5 months), C57BL/6 mice were randomized to control or high DBI polypharmacy treatment (simvastatin, metoprolol, oxybutynin, oxycodone, citalopram) (n=6-8/group) for 4-6 weeks. Compared to control, polypharmacy reduced physical function (grip strength, rotarod latency, gait speed, total distance), middle zone distance (increased anxiety) and nesting score (reduced activities of daily living) in mice of both ages and sexes (p<0.001). Old animals had a greater decline in nesting score (p<0.05) and midzone distance (p<0.001) than young animals. Grip strength declined more in males than females (p<0.05). Drug levels at steady state were not significantly different between polypharmacy-treated animals of both ages and sexes. We observed polypharmacy-induced functional impairment in both age and sex groups, with age and sex interactions in the degree of impairment, which were not explained by serum drug levels. Studies of pathogenesis of the functional impairment from polypharmacy may improve management strategies in both sexes.