Monthly Publication Highlights a Novel Two-Drug Cocktail for Excess Cholesterol Elimination
August 10, 2015
An innovative two-drug approach to helping to eliminate cholesterol from the human body has been named the UK College of Pharmacy Research Publication Highlight for July 2015.
The article was published in the Journal of Lipid Research and is entitled, “The combination of ezetimibe and ursodiol promotes fecal sterol excretion and reveals a G5G8-independent pathway for cholesterol elimination.”
This project was conducted by Greg Graf and Markos Leggas, Associate Professors in the College’s Department of Pharmaceutical Sciences. The first author is Yuhuan Wang, a graduate student in the Graf Laboratory. Additional graduate students contributing to the project include Xiaoxi Liu, Sonja Pijut and Jianing Li. Contributions were also made by staff scientist, Jamie Horn in the Leggas Laboratory as well as Emily Bradford and Terrence Barrett from the Department of Internal Medicine in the College of Medicine.
Tissue and plasma levels of cholesterol are tightly controlled by a complex network that regulates the rates of synthesis, absorption and elimination. While there are a number of therapeutic options to inhibit synthesis and absorption to oppose the development of atherosclerotic disease, there are no effective therapeutics that accelerate cholesterol elimination and, theoretically, reverse atherosclerosis. Cholesterol is primarily eliminated from the body through secretion into bile by the ABCG5 ABCG8 sterol transporter (G5G8) or following its metabolism to bile acids, both of which are briefly stored in the gall bladder before being emptied into the small intestine following meals. However, not all of the secreted cholesterol leaves the body as much of it can be re-absorbed along with dietary cholesterol. The current research describes the combined effect of two drugs, ursodiol and ezetimibe (both FDA approved). Ursodiol increases G5G8 and stimulates bile flow, thereby promoting increased secretion of cholesterol from the liver. Ezetimibe, blocks cholesterol absorption in the small intestine, thereby preventing biliary cholesterol from being re-absorbed. When used together, the effect is to dramatically increase the amount of cholesterol eliminated from the body.
“The investigative team is following up this preclinical research by conducting a small clinical study in human subjects to begin to evaluate the efficacy of this combination therapy,” said Linda Dwoskin, Associate Dean for Research.