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Drug Metabolism and Pharmacokinetics Fellowship Program

Research Background

Dr. Halpert's research for the past 30 years has focused on the structure and function of cytochromes P450. Heterogeneity in the expression levels and/or activities of these important drug-metabolizing enzymes is a major determinant of individual response to medications and likely contributes to individual susceptibility to environmental toxicants as well. Because many of the failures in investigational drug development result from suboptimal pharmacokinetics, drug interactions, and/or toxicity, methods for predicting cytochrome P450-mediated metabolism of new compounds are currently in great demand. Progress in this area is dependent on sophisticated understanding of the structural determinants and mechanisms of cytochrome P450 function.

Area of Fellowships: Mechanisms of Drug Metabolism

1. The mammalian cytochrome P450 2B (CYP2B) subfamily metabolizes a wide range of important compounds, including drugs and environmental contaminants. X-ray crystallographic studies of the rabbit cytochrome P450 2B4 (CYP2B4) by our research group suggest that conformational plasticity and induced fit play an important role in the ability of the enzyme to accommodate such chemically different substrates. Studies are also underway using NMR, mass spectrometry, and molecular modeling to delineate the structural basis of CYP2B ligand binding specificity. Studies on CYP2B enzymes represent a prototype and model for mammalian cytochromes P450 that will improve predictions of in vitro metabolism.
2. Human cytochromes P450 3A (CYP3A) represent a major subfamily of drug-metabolizing enzymes. CYP3A4 metabolizes more known drugs than any other human P450 and is involved in many serious drug interactions. The complicated kinetics often exhibited has stymied efforts to predict metabolism by the enzyme. A variety of biophysical approaches are being employed to understand the mechanistic basis of CYP3A4 function. These approaches include pressure-perturbation spectroscopy, fluorescence resonance energy transfer, and absorbance spectroscopy. Ultimately, these studies will improve the safety of drugs and lead to more effective administration of drug combinations.

Fellowship Program Objectives:

• Coursework/Training
  • Drug metabolism with particular focus on drug-metabolizing cytochromes P450
  • Correlating in vitro studies to in vivo drug metabolism
  • Implications of drug metabolism in drug discovery and development
  • Application of biochemical and biophysical techniques to drug-metabolizing P450 enzymes
  • Career development for industry and academic positions including strategies for applying and interviewing
• Participation in national/international conferences
• Formal/informal collaborations with other laboratories at UCSD and nearby research institutes, such as Scripps

Unique skills fellows will acquire during the program:

Predicting and controlling drug metabolism by cytochromes P450 represents a major roadblock to the development of drugs of high efficacy and safety. A fellow studying these enzymes will have an opportunity to unravel their complex chemical reactions and explore a diverse array of biophysical techniques including advanced fluorescence and absorbance spectroscopy, X-ray crystallography, NMR, computer modeling, and mass spectrometry.