UNRAVELING THE FUNCTIONS OF DETOXIFICATION ENZYMES AND DRUG TRANSPORTERS

Abstract

A number of detoxification systems with broad substrate specificity, including drug transporters and drug-metabolizing enzymes, can protect the body from various toxins, and dramatically influence drug absorption, metabolism, distribution and elimination (ADME) processes, as well as in some cases physiological homeostasis. In Part I of this thesis, in view of the likely importance of the Carboxylesterase 2 enzyme in pharmacological and physiological processes, we generated and characterized several CES2-related genetically modified mouse models. We then demonstrated the value of these mouse models to investigate the pharmacological and physiological functions of the CES2 enzyme complex. In Part II of this thesis we explored and revealed the roles (especially in the blood-brain-barrier) of several drug transporters (ABCB1, ABCG2 and OATP1A/1B) and the drug-metabolizing CYP3A enzymes in pharmacokinetic behavior of several anti-tumor small-molecule inhibitors, as well as related drug-drug interaction effects. We believe that the obtained new mouse models and pharmacological and physiological insights will provide further useful information and support for improving drug discovery and development, and eventually clinical-therapeutic application regimens.