title: Influence of route of administration and lipidation of apolipoprotein A-I peptide on pharmacokinetics and cholesterol mobilization.
abstract: 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 (T1/2= 6.27 h) than for free 22A (T1/2= 3.81 h). The percentage of 22A absorbed by the vascular compartment after the IP dosing was ∼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. Hence, both the route of administration and the formulation of apoA-I peptide significantly affect its pharmacokinetics and pharmacodynamics.
authors.affiliation: Department of Pharmaceutical Sciences North Campus Research Complex, University of Michigan, Ann Arbor, MI.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Pharmaceutical Sciences North Campus Research Complex, University of Michigan, Ann Arbor, MI.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Medicinal Chemistry, North Campus Research Complex, University of Michigan, Ann Arbor, MI.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Drake
authors.affiliation: Department of Pharmaceutical Sciences North Campus Research Complex, University of Michigan, Ann Arbor, MI.
authors.forename: Wenmin
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Department of Pharmaceutical Sciences North Campus Research Complex, University of Michigan, Ann Arbor, MI.
authors.forename: Sara
authors.initials: S
authors.lastname: Deschaine
authors.affiliation: Department of Pharmaceutical Sciences North Campus Research Complex, University of Michigan, Ann Arbor, MI.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Morin
authors.affiliation: Department of Pharmaceutical Sciences North Campus Research Complex, University of Michigan, Ann Arbor, MI.
authors.forename: Rose
authors.initials: R
authors.lastname: Ackermann
authors.affiliation: Department of Pharmaceutical Sciences North Campus Research Complex, University of Michigan, Ann Arbor, MI.
authors.forename: Karl
authors.initials: K
authors.lastname: Olsen
authors.affiliation: Department of Pharmaceutical Sciences North Campus Research Complex, University of Michigan, Ann Arbor, MI.
authors.forename: David E
authors.initials: DE
authors.lastname: Smith
authors.affiliation: Department of Pharmaceutical Sciences North Campus Research Complex, University of Michigan, Ann Arbor, MI annaschw@med.umich.edu.|Department of Medicinal Chemistry, North Campus Research Complex, University of Michigan, Ann Arbor, MI.
authors.forename: Anna
authors.initials: A
authors.lastname: Schwendeman
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D016632:Apolipoprotein A-I / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D007274:Injections, Intraperitoneal; D008075:Lipoproteins, HDL / Q000378:metabolism*; D010455:Peptides / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D051381:Rats
chemical_list: D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D010455:Peptides; D002784:Cholesterol
keywords: HDL; PK-PD modeling; apolipoprotein A-I mimetic peptides; lipoprotein remodeling; lipoproteins/metabolism