期刊
JOURNAL OF LIPID RESEARCH
卷 58, 期 1, 页码 124-136出版社
ELSEVIER
DOI: 10.1194/jlr.M071043
关键词
HDL; lipoproteins/metabolism; apolipoprotein A-I mimetic peptides; lipoprotein remodeling; PK-PD modeling
资金
- American Heart Association [AHA 13SDG17230049, AHA 16POST27760002]
- Michigan College of Pharmacy Upjohn Award
- National Institutes of Health [R01 GM113832, R21 NS091555]
- Cellular Biotechnology Training Program [T32 GM008353]
- Translational Cardiovascular Research and Entrepreneurship Training Grant [T32 HL125242]
- Pharmacological Sciences Training Program [T32 GM07767]
- Interdisciplinary Research Experiences for Undergraduates Program in the Structure and Function of Proteins (National Science Foundation Division of Biological Infrastructure) [1263079]
- Div Of Biological Infrastructure
- Direct For Biological Sciences [1263079] Funding Source: National Science Foundation
apoA-I, apoA-I mimetic peptides, and their lipid complexes or reconstituted high-density lipoprotein (HDL) have been studied as treatments for various pathologies. However, consensus is lacking about the best method for administration, by intravenous (IV) or intraperitoneal (IP) routes, and formulation, as an HDL particle or in a lipid-free form. The objective of this study was to systematically examine peptide plasma levels, cholesterol mobilization, and lipoprotein remodeling in vivo following administration of lipid-free apoA-I peptide (22A) or phospholipid reconstituted 22A-sHDL by IV and IP routes. The mean circulation half-life was longer for 22A-sHDL (T-1/2 = 6.27 h) than for free 22A (T-1/2 = 3.81 h). The percentage of 22A absorbed by the vascular compartment after the IP dosing was similar to 50% for both 22A and 22A-sHDL. The strongest pharmacologic response came from IV injection of 22A-sHDL, specifically a 5.3-fold transient increase in plasma-free cholesterol (FC) level compared with 1.3-and 1.8-fold FC increases for 22A-IV and 22A-sHDL-IP groups. Addition of either 22A or 22A-sHDL to rat plasma caused lipoprotein remodeling and appearance of a lipid-poor apoA-I.(Jlr) Hence, both the route of administration and the formulation of apoA-I peptide significantly affect its pharmacokinetics and pharmacodynamics.
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