Investigation of novel penetration modifiers as enhancers and retardants and human pharmacokinetics and pharmacodynamics of orally administered Quercetin

The delivery of the actives through the outermost layer of the skin, the stratum corneum has posed a challenge for scientists for a very long time. There are compound called “enhancers” that have been developed to enhance drug delivery across skin and at the same time there are compounds referred to as “retardants” that prevent or retard the delivery of actives across the skin. Since both enhancers and retardants are believed to act by modifying the properties of the SC barrier, they are collectively referred to as “penetration modifiers”. The first part of the study aimed at investigating five penetration modifiers that are analogues of laurocapram and iminosulfurane. These penetration modifiers were evaluated initially for their enhancement/retardation potential by computer modeling and investigated for their physical attributes (solubility, lipophilicity, etc.) and formulation effects. The effect of permeation modifier formulations (prepared in commonly used pharmaceutical vehicles) on permeation of model permeants were evaluated and mechanistic studies were performed using thermal, spectral and microscopic analyses. The penetration modifiers were also assessed for their in vitro permeation and cytotoxicity using MTS assay. These investigations should lead to a better understanding of the properties, effects and mechanisms of action of penetration modifiers. The second part of the dissertation covers human pharmacokinetics and pharmacodynamics of quercetin. Quercetin is a naturally occurring flavonoid with antioxidant and anti-inflammatory potential. In order to assess some of benefits of quercetin, this investigation examined the pharmacokinetics and pharmacodynamics of orally administered formulations to human healthy volunteers. Initially, we developed and validated a quercetin assay in human plasma and urine followed by selection of suitable oral carrier for pharmacodynamics study based on pharmacokinetic profiles of three nutritional carrier systems. This was followed by determination of the effects of quercetin supplementation on improving maximal oxygen uptake, enhancing exercise performance during heat stress and relief of muscle soreness. We expect to make conclusions regarding effects of quercetin in overall improvement in work performance of human subjects that would in turn enable the U.S. Department of Defense to consider inclusion of quercetin in daily rations for soldiers to further improve their performance.Ph.D.Includes bibliographical referencesIncludes vitaby Diksha Kaushi