Clinical Pharmacokinetics

, Volume 44, Issue 2, pp 187–200 | Cite as

The Hepatic Sinusoid in Aging and Cirrhosis

Effects on Hepatic Substrate Disposition and Drug Clearance
  • David G. Le Couteur
  • Robin Fraser
  • Sarah Kilmer
  • Laurent P. Rivory
  • Allan J. McLean
Review Article

Abstract

The fenestrated sinusoidal endothelium (‘liver sieve’) and space of Disse in the healthy liver do not impede the transfer of most substrates, including drugs and oxygen, from the sinusoidal lumen to the hepatocyte. Plasma components transfer freely in both directions through the endothelial fenestrations and into the space of Disse. The endothelium is attenuated, there is no basement membrane and there is minimum collagen in the space of Disse, thus minimising any barriers to substrate diffusion.

Both cirrhosis and aging are associated with marked structural changes in the sinusoidal endothelium and space of Disse that are likely to influence bulk plasma transfer into the space of Disse, and diffusion through the endothelium and space of Disse. These changes, termed capillarisation and pseudocapillarisation in cirrhosis and aging, respectively, impede the transfer of various substrates. Capillarisation is associated with exclusion of albumin, protein-bound drugs and macromolecules from the space of Disse, and the progressive transformation of flow-limited to barrier-limited distribution of some substrates.

There is evidence that the sinusoidal changes in cirrhosis and aging contribute to hepatocyte hypoxia, thus providing a mechanism for the apparent differential reduction of oxygen-dependent phase I metabolic pathways in these conditions. Structural change and subsequent dysfunction of the liver sieve warrant consideration as a significant factor in the impairment of overall substrate handling and hepatic drug metabolism in cirrhosis and aging.

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Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  • David G. Le Couteur
    • 1
  • Robin Fraser
    • 2
  • Sarah Kilmer
    • 1
  • Laurent P. Rivory
    • 3
  • Allan J. McLean
    • 4
  1. 1.Centre for Education and Research on Ageing and ANZAC Research InstituteUniversity of SydneySydneyAustralia
  2. 2.Department of Pathology, Christchurch School of Medicine and Health SciencesUniversity of OtagoChristchurchNew Zealand
  3. 3.Department of PharmacologyUniversity of SydneyNew South WalesAustralia
  4. 4.National Ageing Research Institute, and Department of Medicine, Royal Melbourne HospitalUniversity of Melbourne and Melbourne HealthParkvilleAustralia

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