Drugs & Aging

, Volume 18, Issue 11, pp 837–851 | Cite as

Liver Function and Phase I Drug Metabolism in the Elderly

A Paradox
Review Article

Abstract

Aging is accompanied by marked changes in the physiology of many organs, as well as in their constituent cells. These nonpathological alterations in structure and/or function may affect normal physiological processes in the elderly (individuals >65 years), for example drug disposition. The liver plays a major role in drug clearance and aging has been reported to diminish this hepatic capacity, particularly the clearance of drugs that undergo mandatory oxidation by the microsomal cytochrome P450-dependent mono-oxygenase systems. Liver volume and blood flow decline with age in humans and, no doubt, this contributes to the diminished clearance of drugs that exhibit first-pass kinetic profiles.

Changes in liver morphology with aging that have been described in rodents are limited to the hepatocytes, for example accumulation of dense bodies and loss of smooth surfaced endoplasmic reticulum. There is no evidence that the increase in intracellular lipofuscin adversely affects hepatocyte functions. A number of studies have documented significant age-related declines in the amounts, specific activities and rates of induction of liver microsomal mono-oxygenases in inbred male rats.

On the basis of a variety of clinical tests, most liver functions in humans appear to be well preserved. The most remarkable characteristic of liver function in the elderly is the increase in interindividual variability, a feature that may obscure age-related differences. Most in vitro studies using nonhuman primate or human liver tissue did not detect age-related deficiencies in cytochrome P450-dependent microsomal mono-oxygenases. On the other hand, there have been recent reports of age-related, but not gender-related, declines in the in vitro activities of several human liver mono-oxygenases, for example the cytochrome P450 isoform CYP3A. Nevertheless, reduced liver volume and blood flow in the elderly permit the reconciliation of: (i) the in vivo clinical pharmacokinetic data indicative of reduced hepatic drug clearance; and (ii) the absence of significant age-related declines in the amounts or in vitro activities of liver microsomal mono-oxygenases.

Keywords

Liver Volume Hepatic Blood Flow Hepatic Clearance NADPH Cytochrome P450 Reductase Brofaromine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

There are no potential conflicts of interest that are directly relevant to the contents of this manuscript. This research was supported by a US Department of Veterans Affairs Merit Review grant awarded to D.L. Schmucker. Dr Schmucker is a Senior Career Research Scientist in the Department of Veterans Affairs.

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© Adis International Limited 2001

Authors and Affiliations

  1. 1.Cell Biology & Aging Section (151E)Veterans Affairs Medical CenterSan FranciscoUSA
  2. 2.Department of Anatomy and the Liver CenterUniversity of CaliforniaSan FranciscoUSA

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