Fish oil and flax seed oil supplemented diets increase FFAR4 expression in the rat colon.

BACKGROUND AND OBJECTIVE: Omega-3 fatty acids, such as α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), are polyunsaturated fatty acids (PUFA) that have long been associated with anti-inflammatory activity and general benefit toward human health. Over the last decade, the identification of a family of cell-surface G protein-coupled receptors that bind and are activated by free-fatty acids, including omega-3 fatty acids, suggest that many effects of PUFA are receptor-mediated. One such receptor, free-fatty acid receptor-4 (FFAR4), previously described as GPR120, has been shown to modulate anti-inflammatory and insulin-sensitizing effects in response to PUFA such as ALA and DHA. Additionally, FFAR4 stimulates secretion of the insulin secretagogue glucagon-like peptide-1 (GLP-1) from the GI tract and acts as a dietary sensor to regulate energy availability. The aim of the current study was to assess the effects of dietary omega-3 fatty acid supplementation on FFAR4 expression in the rat colon. METHODS: Sprague-Dawley rats were fed control soybean oil diets or alternatively, diets supplemented with either fish oil, which is enriched in DHA and EPA, or flaxseed oil, which is enriched in ALA, for 7 weeks. GLP-1 and blood glucose levels were monitored weekly and at the end of the study period, expression of FFAR4 and the inflammatory marker TNF-α was assessed. RESULTS: Our findings indicate that GLP-1 and blood glucose levels were unaffected by omega-3 fatty acid supplementation, however, animals that were fed fish or flaxseed oil-supplemented diets had significantly heightened colonic FFAR4 and actin expression, and reduced expression of the pro-inflammatory cytokine TNF-α compared to animals fed control diets. CONCLUSIONS: These results suggest that similar to ingestion of other fats, dietary-intake of omega-3 fatty acids can alter FFAR4 expression within the colon.

Formulation of a danazol cocrystal with controlled supersaturation plays an essential role in improving bioavailability.

Cocrystals have become an established and adopted approach for creating crystalline solids with improved physical properties, but incorporating cocrystals into enabling pre-clinical formulations suitable for animal dosing has received limited attention. The dominant approach to in vivo evaluation of cocrystals has focused on deliberately excluding additional formulation in favor of "neat" aqueous suspensions of cocrystals or loading neat cocrystal material into capsules. However, this study demonstrates that, in order to take advantage of the improved solubility of a 1:1 danazol:vanillin cocrystal, a suitable formulation was required. The neat aqueous suspension of the danazol:vanillin cocrystal had a modest in vivo improvement of 1.7 times higher area under the curve compared to the poorly soluble crystal form of danazol dosed under identical conditions, but the formulated aqueous suspension containing 1% vitamin E-TPGS (TPGS) and 2% Klucel LF Pharm hydroxypropylcellulose improved the bioavailability of the cocrystal by over 10 times compared to the poorly soluble danazol polymorph. In vitro powder dissolution data obtained under non-sink biorelevant conditions correlate with in vivo data in rats following 20 mg/kg doses of danazol. In the case of the danazol:vanillin cocrystal, using a combination of cocrystal, solubilizer, and precipitation inhibitor in a designed supersaturating drug delivery system resulted in a dramatic improvement in the bioavailability. When suspensions of neat cocrystal material fail to return the anticipated bioavailability increase, a supersaturating formulation may be able to create the conditions required for the increased cocrystal solubility to be translated into improved in vivo absorption at levels competitive with existing formulation approaches used to overcome solubility limited bioavailability.