Are drug-triglyceride conjugates formed endogenously in the intestine?
Drugs with carboxylic acid functional groups can be recognized by enzymes that metabolize fatty acids. This can result in formation of drug-lipid conjugates such as triglyceride (TG), phospholipid or cholesterol ester like compounds (1). For example, 4.5-9% of the anti-inflammatory ibuprofen in the blood circulates in the form of a TG conjugate. Ibuprofen is esterified to glycerides in fat where ibuprofen-TG conjugate concentrations are ~20 fold higher than in the blood. Despite this literature no studies have previously explored whether drug-TG conjugates are formed in the intestine and drug-TG conjugate formation has only been explored for a limited number of drug classes. This is surprising given that the intestine re-synthesizes TG from dietary fatty acids and glycerides in substantial amounts every day. This knowledge is important as drug-TG conjugate formation will influence the route of drug absorption from the intestine (lymph vs blood) (2), drug distribution to sites of lipid storage (e.g. fat, liver) and ultimately drug distribution to target and off-target tissues where therapeutic and toxic effects are mediated. This project will determine the efficiency of drug-TG formation for a range of drug substrates with different structures and will investigate the role of the intestine when compared to other tissues (fat, liver etc) in drug-TG formation. The student will learn a range of laboratory skills such as cell and tissue culture, LC-MS-MS analysis and fluorescent imaging. The data will inform design criteria for drugs, particularly those for diseases promoted by disturbances in lipid metabolism such as obesity, atherosclerosis and type 2 diabetes. 1. Fears, Prog Lipid Res. Vol. 24, pp. 177-195, 1985