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Research ArticleCardiovascular

Phospholipid component defines pharmacokinetic and pharmacodynamic properties of synthetic high-density lipoproteins

Maria V. Fawaz, Sang Yeop Kim, Dan Li, Ran Ming, Ziyun Xia, Karl Olsen, Irina D. Pogozheva, John J. G. Tesmer and Anna Schwendeman
Journal of Pharmacology and Experimental Therapeutics November 27, 2019, jpet.119.257568; DOI: https://doi.org/10.1124/jpet.119.257568
Maria V. Fawaz
1 University of Michigan;
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Sang Yeop Kim
1 University of Michigan;
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Dan Li
1 University of Michigan;
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Ran Ming
1 University of Michigan;
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Ziyun Xia
1 University of Michigan;
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Karl Olsen
1 University of Michigan;
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Irina D. Pogozheva
1 University of Michigan;
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John J. G. Tesmer
2 Purdue University
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Anna Schwendeman
1 University of Michigan;
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Abstract

Synthetic high-density lipoprotein (sHDL) nanoparticles composed of apolipoprotein A-I (ApoA-I) mimetic peptide and phospholipids have been shown to reduce atherosclerosis in animal models. Cholesterol is mobilized from atheroma macrophages by sHDL into the blood compartment and delivered to the liver for elimination. Historically, sHDL drug discovery efforts were focused on optimizing peptide sequence for interaction with cholesterol cellular transporters rather than understanding how both sHDL components, peptide and lipid, influence its pharmacokinetics (PK) and pharmacodynamic (PD) profiles. We designed two sets of sHDL having either identical phospholipid but variable peptide sequences with different plasma stability, or identical peptide and phospholipids with variable fatty acid chain length and saturation. We found that sHDL prepared with proteolytically stable 22A-P peptide had 2-fold longer circulation half-time relative to the less stable 22A peptide. Yet, longer half-life did not translate into any improvement in cholesterol mobilization. In contrast, sHDL with variable phospholipid compositions showed significant differences in phospholipid PK, with distearoyl phosphatidylcholine-based sHDL demonstrating the longest half-life of 6.0 h relative to 1.0 h for palmitoyl-oleoyl phosphatidylcholine-based sHDL. This increase in half-life corresponded to a ~6.5-fold increase in the area under the curve for the mobilized cholesterol. Therefore, the phospholipid component in sHDL plays a major role in cholesterol mobilization in vivo and should not be overlooked in the design of future sHDL.

SIGNIFICANCE STATEMENT The phospholipid composition in sHDL plays a critical role in determining half-life and cholesterol mobilization in vivo.

  • cardiovascular disease
  • cardiovascular drugs
  • cholesterol
  • cholesterol metabolism/lipoproteins
  • lipids
  • lipoproteins
  • nanoparticles
  • pharmacodynamics
  • pharmacokinetics
  • phospholipid metabolism
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 2
1 Feb 2021
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Research ArticleCardiovascular

Phospholipid component defines pharmacokinetic and pharmacodynamic properties of synthetic high-density lipoproteins

Maria V. Fawaz, Sang Yeop Kim, Dan Li, Ran Ming, Ziyun Xia, Karl Olsen, Irina D. Pogozheva, John J. G. Tesmer and Anna Schwendeman
Journal of Pharmacology and Experimental Therapeutics November 27, 2019, jpet.119.257568; DOI: https://doi.org/10.1124/jpet.119.257568

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Research ArticleCardiovascular

Phospholipid component defines pharmacokinetic and pharmacodynamic properties of synthetic high-density lipoproteins

Maria V. Fawaz, Sang Yeop Kim, Dan Li, Ran Ming, Ziyun Xia, Karl Olsen, Irina D. Pogozheva, John J. G. Tesmer and Anna Schwendeman
Journal of Pharmacology and Experimental Therapeutics November 27, 2019, jpet.119.257568; DOI: https://doi.org/10.1124/jpet.119.257568
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