Intestine may be a major site of action for the apoA-I mimetic peptide 4F whether administered subcutaneously or orally

Mohamad Navab,Srinivasa T Reddy,G.M Anantharamaiah,Satoshi Imaizumi,Greg Hough,Susan Hama,Alan M Fogelman

doi:10.1194/jlr.m013144

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.

Highlights

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 4F synthesized from all D-amino acids (D-4F) were administered orally or subcutaneously (SQ) to apoliptoteinE null mice
Based on three lines of evidence [ i) the peptide plasma levels in the study by Bloedon et al (3), which were associated with a significant improvement in HDL-inflammatory index (HII); ii) the peptide plasma levels achieved in animal studies demonstrating efficacy (4); and iii) D-4F added at a concentration of 250 ng/ml to the plasma of patients with coronary heart disease (CHD) significantly improved HII (1)], Watson et al (5) designed studies of 4F synthesized from all L-amino acids (L-4F) in patients with CHD to achieve pretargeted peptide plasma levels
A plasma sample from an apoE null mouse that had not received peptide was spiked with D-4F to give a plasma concentration of 1,000, 200, 40, 10, or 1 ng/ml

Summary

Introduction

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. A dose of 45 mg/kg/day administered to apoE null mice on a Western diet reduced aortic atherosclerosis by ‫ف‬50% (P < 0.0009) whether administered orally or SQ and significantly reduced plasma levels of SAA (P < 0.002) and lysophosphatidic acid (P < 0.0009). 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.—Navab, M., S. When this peptide was synthesized from all D-amino acids (D-4F) and

Methods

Results

Conclusion