Review Article Special Populations

Clinical Pharmacokinetics

, Volume 34, Issue 5, pp 359-373

The Aging Liver

Drug Clearance and an Oxygen Diffusion Barrier Hypothesis
  • David G. Le CouteurAffiliated withUniversity Department of Medicine and ACT Health Department of Geriatric Medicine, The Canberra Clinical School of the University of Sydney, The Canberra Hospital
  • , Allan J. McLeanAffiliated withUniversity Department of Medicine and ACT Health Department of Geriatric Medicine, The Canberra Clinical School of the University of Sydney, The Canberra Hospital Email author 

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Abstract

A change in drug clearance with age is considered an important factor in determining the high prevalence of adverse drug reactions associated with prescribing medications for the elderly. Despite this, no general principles have been available to guide drug administration in the elderly, although a substantial body of clearance and metabolism data has been generated in humans and experimental animals. A review of age-related change in drug clearances established that patterns of change are not simply explained in terms of hepatic blood flow, hepatic mass and protein binding changes. In particular, the maintained clearance of drugs subject to conjugation processes while oxygen-dependent metabolism declines, and all in vitro tests of enzyme function have been normal, requires new explanations.

Reduction in hepatic oxygen diffusion as part of a general change in hepatocyte surface membrane permeability and conformation does provide one explanation for the paradoxical patterns of drug metabolism, and increased hepatocyte volume would also modify oxygen diffusion path lengths (the ‘oxygen diffusion barrier’ hypothesis). The reduction in clearances of high extraction drugs does correlate with observed reduction in hepatic perfusion.

Dosage guidelines emerge from these considerations. The dosage of high clearance drugs should be reduced by approximately 40% in the elderly while the dosage of low clearance drugs should be reduced by approximately 30%, unless the compound is principally subject to conjugation mechanisms. If the hepatocyte diffusion barrier hypothesis is substantiated, this concept may lead to therapeutic (preventative and/or restorative) approaches to increased hepatocyte oxygenation in the elderly. This may lead to approaches for modification of the aging process in the liver.