Drug metabolism in older people--a key consideration in achieving optimal outcomes with medicines.

Hepatic clearance plays a key role in determining the systemic exposure of drugs and metabolites, which in turn has a major effect on variability in the beneficial and adverse effects of medicines. Aging results in a number of significant changes in the human liver including reductions in liver blood flow, size, drug-metabolizing enzyme content, and pseudocapillarization. Drug metabolism is also influenced by comorbid disease, frailty, concomitant medicines, and (epi)genetics. These changes have the potential to alter the hepatic clearance of drugs but need to be interpreted in the context of the pharmacokinetic (and pharmacodynamic) characteristics of the drug of interest. There is growing evidence that the age-related changes in the liver not only result in a decrease in the hepatic clearance of unbound drug but also influence variability in response to medicines in older people.