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  • Review Article
  • Published:

Impact of lipoproteins on the biological activity and disposition of hydrophobic drugs: implications for drug discovery

Nature Reviews Drug Discovery volume 7, pages 84–99 (2008)Cite this article

Key Points

  • This review discusses the impact of hydrophobic drug-lipoprotein interactions on pharmacokinetics, drug metabolism, tissue distribution and biological activity of various hydrophobic compounds, and the importance of using this information in drug discovery and development programmes.

  • The nature of drug interaction with lipoproteins might differ from that of binding to other proteins, which is to a large degree attributable to the unique nature of lipoproteins. As the composition of circulating lipoproteins can be modified in various physiological or pathophysiological states, it is possible that a change in the extent of drug binding in plasma might ensue.

  • Drugs that bind to lipoproteins are most likely to be highly lipophilic and are often prime candidates for drug metabolism as a major pathway of elimination from the body. Examples of drugs with high log P values that are known to bind to lipoproteins include cyclosporine A, amiodarone, halofantrine, amphotericin B, nystatin and eritoran.

  • In evaluating the effects of increased plasma lipid content on the pharmacokinetics of drugs, it is important to consider the nature of the cause of the increased lipid levels. The inconsistencies between studies in the observed outcomes of hyperlipidaemia and pharmacokinetics can be attributed to a number of factors, including the experimental species, the model of hyperlipidaemia, postprandial state or other experimental issues relating to research design and implementation.

  • From the perspective of drug discovery, it is possible that within a series of new drug entities, the ones that are more lipophilic might have a greater relative degree of potency, due to their greater ability to gain access to the target proteins for pharmacological activity. In turn, drugs with high log P are better candidates for association with plasma lipoproteins.

  • In the Western world, where obesity and diabetes are now present in epidemic proportions, there are likely to be more individuals in the population with high levels of circulating lipoproteins, which might modify the pharmacokinetic behaviours, and ultimately, the pharmacological activities of the drugs candidates.

  • By understanding the uptake mechanisms of specific drugs into lipoproteins, and the influence that novel delivery systems can impart into the lipoprotein distribution of drug, there are potential opportunities to improve the therapeutic profiles of such drugs, thereby optimizing the drug development process, and ultimately, patient outcomes.

Abstract

In contrast to many traditional pharmaceutical agents that exhibit a high degree of aqueous solubility, new drug candidates are frequently highly lipophilic compounds. The aqueous environment of the blood provides a thermodynamically unfavourable environment for the disposition of such hydrophobic drugs. However, this limitation can be overcome by association with circulating lipoproteins. Elucidation of the mechanisms that dictate drug–lipoprotein association and blood-to-tissue partitioning of lipoprotein encapsulated drugs might yield valuable insight into the factors governing the pharmacological activity and potential toxicity of these compounds. This Review discusses the impact of hydrophobic drug–lipoprotein interactions on pharmacokinetics, drug metabolism, tissue distribution and biological activity of various hydrophobic compounds, and outlines how best to use this information in drug discovery and development programmes.

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Figure 1: General structure of a lipoprotein.
Figure 2: Lipoprotein metabolism.
Figure 3: Drug interactions with biological components.
Figure 4: LDL receptor family.
Figure 5: Diagram of the LDL receptor-mediated endocytosis pathway.

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Acknowledgements

We would like to thank the many colleagues, mentors and collaborators that have supported this research area over the years. In particular, we would like to thank G. Lopez-Berestein, A. C. Hayman, R. E. Morton and P. H. Pritchard. We would also like to thank the Canadian Institutes of Health Research for the many years of funding to K.M.W. and D.R.B.

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  1. Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, V6T 1Z3, Canada

    Kishor M. Wasan, Stephen D. Lee, Kristina Sachs-Barrable & Sheila J. Thornton

  2. Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, T6G 2N8, Canada

    Dion R. Brocks

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DATABASES

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Autosomal dominant familial hypertriglyceridaemia

Familial combined hyperlipidaemia

Hypercholesterolaemia

Schizophrenia

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Wasan, K., Brocks, D., Lee, S. et al. Impact of lipoproteins on the biological activity and disposition of hydrophobic drugs: implications for drug discovery. Nat Rev Drug Discov 7, 84–99 (2008). https://doi.org/10.1038/nrd2353

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