title: Intestine may be a major site of action for the apoA-I mimetic peptide 4F whether administered subcutaneously or orally.
abstract: To determine if the dose of peptide administered or the plasma level was more important, doses of 0.15, 0.45, 4.5, or 45 mg/kg/day of the peptide D-4F were administered orally or subcutaneously (SQ) to apoliptotein (apo)E null mice. Plasma levels of peptide were ∼1,000-fold higher when administered SQ compared with orally. Regardless of the route of administration, doses of 4.5 and 45 mg/kg significantly reduced plasma serum amyloid A (SAA) levels and the HDL inflammatory index (P < 0.0001); doses of 0.15 or 0.45 mg/kg did not. A dose of 45 mg/kg/day administered to apoE null mice on a Western diet reduced aortic atherosclerosis by ∼50% (P < 0.0009) whether administered orally or SQ and also significantly reduced plasma levels of SAA (P < 0.002) and lysophosphatidic acid (P < 0.0009). Remarkably, for each dose administered, the concentration and amount of peptide in the feces was similar regardless of whether the peptide was administered orally or SQ. We conclude: i) the dose of 4F administered and not the plasma level achieved determines efficacy; ii) the intestine may be a major site of action for the peptide regardless of the route of administration.
authors: Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095. Electronic address: mnavab@mednet.ucla.edu.
authors: Mohamad
authors: M
authors: Navab
authors: Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095.
authors: Srinivasa T
authors: ST
authors: Reddy
authors: Department of Medicine, University of Alabama, Birmingham, AL 35294.
authors: G M
authors: GM
authors: Anantharamaiah
authors: Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095.
authors: Satoshi
authors: S
authors: Imaizumi
authors: Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095.
authors: Greg
authors: G
authors: Hough
authors: Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095.
authors: Susan
authors: S
authors: Hama
authors: Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095.
authors: Alan M
authors: AM
authors: Fogelman
mesh_terms: D000279:Administration, Cutaneous; D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood* / Q000503:physiopathology / Q000652:urine*; D004032:Diet; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005243:Feces / Q000737:chemistry; D005260:Female; D017353:Gene Deletion; D007249:Inflammation / Q000097:blood / Q000652:urine; D007413:Intestinal Mucosa / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000097:blood; D008099:Liver / Q000378:metabolism; D008246:Lysophospholipids / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010455:Peptides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000685:Serum Amyloid A Protein / Q000032:analysis / Q000096:biosynthesis
chemical_list: D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D010455:Peptides; D000685:Serum Amyloid A Protein; C032881:lysophosphatidic acid