Date of Award

8-2013

Document Type

Thesis

Degree Name

Master of Science (MS)

College/School

College of Science and Mathematics

Department/Program

Biology

Thesis Sponsor/Dissertation Chair/Project Chair

Vladislav Snitsarev

Committee Member

David P. Rotella

Committee Member

John J. Siekierka

Abstract

Sirolimus is one of the most successful immunosuppressant drugs available but it has an extremely low solubility in water that dramatically limits its oral bioavailability to approximately 20%. This study is aimed to increase solubility of Sirolimus in aqueousolutions through complexation with a metal ion. Using computer modeling and UV absorbance spectroscopy, it was demonstrated that 1) Sirolimus interacts with AJ3+,Cu2+, Fe3+ , Mn2+, Zn2+ ; 2) this interaction decreases UV light absorbance of Sirolimus measured at ^=280 nm; 3) a previously reported value of solubility of Sirolimus in water is underestimated; 4) Sirolimus can exist in aqueous solutions in different soluble physical forms, including multimers; 5) complexation of Sirolimus with Al³+ increases its aqueous solubility that potentially can improve its oral bioavailability. Similar approach, i.e. complexation with a metal ion, can be used to increase aqueous solubility of other compounds containing ligands with unshared electron pairs, for example, cyclic macrolides like Tacrolimus, derivatives of Tacrolimus and Sirolimus, as well as peptide drugs such as Cyclosporin A.

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