title: Oral bioavailability of the ether lipid plasmalogen precursor, PPI-1011, in the rabbit: a new therapeutic strategy for Alzheimer's disease.
abstract: BACKGROUND
  Docosahexaenoic acid (DHA) and DHA-containing ethanolamine plasmalogens (PlsEtn) are decreased in the brain, liver and the circulation in Alzheimer's disease. Decreased supply of plasmalogen precursors to the brain by the liver, as a result of peroxisomal deficits is a process that probably starts early in the AD disease process. To overcome this metabolic compromise, we have designed an orally bioavailable DHA-containing ether lipid precursor of plasmalogens. PPI-1011 is an alkyl-diacyl plasmalogen precursor with palmitic acid at sn-1, DHA at sn-2 and lipoic acid at sn-3. This study outlines the oral pharmacokinetics of this precursor and its conversion to PlsEtn and phosphatidylethanolamines (PtdEtn).
  
  
  METHODS
  Rabbits were dosed orally with PPI-1011 in hard gelatin capsules for time-course and dose response studies. Incorporation into PlsEtn and PtdEtn was monitored by LC-MS/MS. Metabolism of released lipoic acid was monitored by GC-MS. To monitor the metabolic fate of different components of PPI-1011, we labeled the sn-1 palmitic acid, sn-2 DHA and glycerol backbone with (13)C and monitored their metabolic fates by LC-MS/MS.
  
  
  RESULTS
  PPI-1011 was not detected in plasma suggesting rapid release of sn-3 lipoic acid via gut lipases. This conclusion was supported by peak levels of lipoic acid metabolites in the plasma 3 hours after dosing. While PPI-1011 did not gain access to the plasma, it increased circulating levels of DHA-containing PlsEtn and PtdEtn. Labeling experiments demonstrated that the PtdEtn increases resulted from increased availability of DHA released via remodeling at sn-2 of phospholipids derived from PPI-1011. This release of DHA peaked at 6 hrs while increases in phospholipids peaked at 12 hr. Increases in circulating PlsEtn were more complex. Labeling experiments demonstrated that increases in the target PlsEtn, 16:0/22:6, consisted of 2 pools. In one pool, the intact precursor received a sn-3 phosphoethanolamine group and desaturation at sn-1 to generate the target plasmalogen. The second pool, like the PtdEtn, resulted from increased availability of DHA released during remodeling of sn-2. In the case of sn-1 18:0 and 18:1 plasmalogens with [(13)C(3)]DHA at sn-2, labeling was the result of increased availability of [(13)C(3)]DHA from lipid remodeling. Isotope and repeated dosing (2 weeks) experiments also demonstrated that plasmalogens and/or plasmalogen precursors derived from PPI-1011 are able to cross both the blood-retinal and blood-brain barriers.
  
  
  CONCLUSIONS
  Our data demonstrate that PPI-1011, an ether lipid precursor of plasmalogens is orally bioavailable in the rabbit, augmenting the circulating levels of unesterified DHA and DHA-containing PlsEtn and PtdEtn. Other ethanolamine plasmalogens were generated from the precursor via lipid remodeling (de-acylation/re-acylation reactions at sn-2) and phosphatidylethanolamines were generated via de-alkylation/re-acylation reactions at sn-1. Repeated oral dosing for 2 weeks with PPI-1011 resulted in dose-dependent increases in circulating DHA and DHA-containing plasmalogens. These products and/or precursors were also able to cross the blood-retinal and blood-brain barriers.
authors.affiliation: Dept, of Pharmacology, DeBusk College of Osteopathic Medicine, Lincoln Memorial University, Harrogate, TN 37752 USA. paul.wood@lmunet.edu
authors.forename: Paul L
authors.initials: PL
authors.lastname: Wood
authors.forename: Tara
authors.initials: T
authors.lastname: Smith
authors.forename: Nina
authors.initials: N
authors.lastname: Lane
authors.forename: M Amin
authors.initials: MA
authors.lastname: Khan
authors.forename: Greg
authors.initials: G
authors.lastname: Ehrmantraut
authors.forename: Dayan B
authors.initials: DB
authors.lastname: Goodenowe
mesh_terms: D000284:Administration, Oral; D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001682:Biological Availability; D002208:Caproates / Q000097:blood; D004075:Diglycerides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004281:Docosahexaenoic Acids / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D010714:Phosphatidylethanolamines / Q000097:blood; D010955:Plasmalogens / Q000097:blood; D011817:Rabbits; D014018:Tissue Distribution
chemical_list: D002208:Caproates; D004075:Diglycerides; D010714:Phosphatidylethanolamines; D010955:Plasmalogens; C002449:glycerophosphoethanolamine; D004281:Docosahexaenoic Acids