| Of the obstacles that prevent accumulation of therapeutic drug levels in systemic circulation, drug metabolism is arguably the most significant. The evasion of drug metabolizing enzymes, or bioevasion, provides a strategy to overcome this common obstacle and therefore holds the potential to greatly benefit pharmaceutical development. Bioevasion as a means to overcoming drug metabolism can be addressed through two complementary approaches: identification of the enzymes and mechanisms responsible for drug metabolism or stabilization of the drug against these enzymes via chemical modification. This dissertation describes the application of this rational, two-pronged approach to the identification of enzymes responsible for metabolism of a nucleoside analog, 2-bromo-5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole (BDCRB), and subsequent application of a prodrug strategy to enhance the metabolic stability of BDCRB.; The susceptibility of BDCRB to glycosidic bond cleavage in vivo has been known for some time, but there have been no reports on the mechanism responsible for its metabolism. The identification of two BDCRB-metabolizing enzymes, 8-oxoguanine DNA glycosylase (OGG1) and N-methylpurine DNA glycosylase (MPG) is described herein. Their activity on nucleoside analogs implies that OGG1 and MPG may create a barrier to effective delivery of other antiviral and anticancer nucleoside analogs.; To overcome this barrier for BDCRB, prodrugs were designed and synthesized to enhance metabolic stability. These amino acid ester prodrugs of BDCRB demonstrated reduced affinity for OGG1 and MPG and enhanced half-life and overall delivery in vivo. This effect could be manipulated by the choice of promoiety due to differential rate of ester bond cleavage, thereby providing a modular approach to achieving bioevasion. Thus, bioevasion represents a comprehensive approach to enhancement of drug delivery through enzyme analysis and rational drug stabilization. |
