D-4F-mediated reduction in metabolites of arachidonic and linoleic acids in the small intestine is associated with decreased inflammation in low-density lipoprotein receptor-null mice

Transintestinal transport of the anti-inflammatory drug 4F and the modulation of transintestinal cholesterol efflux

“…Both oral and subcutaneous (SQ) d-4F at doses of 4.5 and 45 mg/kg significantly improved markers of HDL function and systemic inflammation equally for a given dose, but these modes of administration achieved very different plasma levels of peptide, with SQ levels being 1,000× higher. Rather, the equally effective SQ and oral doses achieved equal concentrations of 4F only in the feces (46) and the SI (5). This finding suggested that the intestine may be the site of action for 4F.…”

Source and role of intestinally derived lysophosphatidic acid in dyslipidemia and atherosclerosis

“…Additionally, we also provide anti-infl ammatory properties and by decreases in plasma serum amyloid A (SAA) levels, but the plasma peptide levels did not predict effi cacy ( 6 ). In the next study, the peptide concentration in the small intestine of LDL receptor null (LDLR Ϫ / Ϫ ) mice on a Western diet (WD) predicted effi cacy as measured by the ability of the peptide to reduce tissue and plasma levels of proinfl ammatory oxidized metabolites of arachidonic and linoleic acids and by plasma SAA levels, but the plasma peptide levels again did not predict effi cacy ( 7 ). In these mouse studies ( 6,7 ), the dose required for effi cacy was far above the highest dose tested in the human clinical trials that did not demonstrate effi cacy ( 5 ).…”

“…Second, there was a mistaken belief that the peptides act primarily in the plasma, and that the level of peptide in plasma was the critical success factor. Our studies subsequent to the third report ( 5 ) suggested that high doses of peptide (40-100 mg/kg/day) must be delivered to the small intestine in order to achieve effi cacy ( 6,7 ). The peptides used in the three reports of human clinical trials ( 3-5 ) contained blocked end groups, which can only be added by chemical synthesis.…”

“…In the next study, the peptide concentration in the small intestine of LDL receptor null (LDLR Ϫ / Ϫ ) mice on a Western diet (WD) predicted effi cacy as measured by the ability of the peptide to reduce tissue and plasma levels of proinfl ammatory oxidized metabolites of arachidonic and linoleic acids and by plasma SAA levels, but the plasma peptide levels again did not predict effi cacy ( 7 ). In these mouse studies ( 6,7 ), the dose required for effi cacy was far above the highest dose tested in the human clinical trials that did not demonstrate effi cacy ( 5 ). Additionally, we noted that the effective dose of these peptides tested in rabbits as measured by improvement in HDL anti-infl ammatory properties, plasma SAA levels, and aortic atherosclerosis was also higher than the doses used in the third study ( 8 ).…”

High-Density Lipoprotein

“…Because the plasma and liver concentrations of peptide after administering the peptide orally were 100-to 1000-fold lesser compared with administering the peptide subcutaneously, these data strongly suggest that the reduction of oxidized metabolites of arachidonic acid in the small intestine by the peptide led to the reduction in liver levels. 107 These results likely explain the failure of the clinical trial by Watson et al 105 The dose administered was likely too low to achieve the needed peptide levels in the small intestine. The results also suggest that a dose of peptide on the order of 40 to 100 mg/kg per day will be required for efficacy.…”