title: Solubility and stability of dalcetrapib in vehicles and biological media.
abstract: Dalcetrapib solubility was determined in aqueous and in non-aqueous vehicles and in biorelevant media. In a pure aqueous environment the solubility was low but could be increased by addition of surfactants or complexing agents. This was also reflected in the solubility seen in simulated gastrointestinal (GI) fluids, with almost no solubility in simulated gastric fluid, but reasonable solubilisation in simulated intestinal fluids containing lecithin and bile salt. Additionally, the stability of dalcetrapib was determined in simulated GI fluids with and without pancreatic lipase. In solutions without lipase, dalcetrapib was slowly hydrolysed, but in the presence of lipase the hydrolysis rate was significantly faster depending on pH and enzyme activity. In biological fluids, dissolved dalcetrapib appeared to behave similarly being rapidly hydrolysed in human intestinal fluids with a half-life below 20s with no degradation observed in human gastric fluids at low pH. The results provide supportive evidence that absorption is higher under fed conditions and indicate lipase inhibitors might interfere with oral absorption of dalcetrapib.
authors.affiliation: F. Hoffmann-La Roche Ltd, Basel, Switzerland. guenter.gross@roche.com
authors.forename: Günter
authors.initials: G
authors.lastname: Gross
authors.forename: Joseph
authors.initials: J
authors.lastname: Tardio
authors.forename: Olaf
authors.initials: O
authors.lastname: Kuhlmann
mesh_terms: D000577:Amides; D000924:Anticholesteremic Agents / Q000737:chemistry*; D001647:Bile Acids and Salts / Q000737:chemistry; D004355:Drug Stability; D004952:Esters; D005750:Gastric Juice / Q000737:chemistry; D006801:Humans; D007419:Intestinal Secretions / Q000737:chemistry; D054709:Lecithins / Q000737:chemistry; D008049:Lipase / Q000737:chemistry; D012463:Saliva / Q000737:chemistry; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013501:Surface-Active Agents / Q000737:chemistry
chemical_list: D000577:Amides; D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D004952:Esters; D054709:Lecithins; D012997:Solvents; D013438:Sulfhydryl Compounds; D013501:Surface-Active Agents; C411602:dalcetrapib; D008049:Lipase; C518354:PNLIP protein, human