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Targeted metabolomics of hepatocyte drug transformation

A major concern in drug development is the potential for chemical injury to the liver, which is the major site of xenobiotic transformation in the body. Unfortunately, such adverse reactions are often only detected after the drug has been released onto the market and not during the drug development or clinical trials, let alone the discovery stage. A number of factors can contribute to the adverse response, including genetic sensitivity, disease state, and nutritional status. Current efforts to assess drug safety and efficacy rely heavily on animal models to bridge the gap between in vitro screening experiments and human trials. The experimental burden and associated costs are likely to rise further with increased use of combination therapies involving multiple drugs to treat the chronic ailments of an aging population. The goal of this research is to develop metabolomic approaches to complement and guide conventional, animal and cell-based studies. Our approach is to combine computational pathway analysis with targeted, but wide-spectrum, measurements of metabolic intermediates, including cofactors. To facilitate the drug exposure experiments, we are currently developing easy-to-fabricate micro-fluidic devices capable of supporting three-dimensional hepatocyte cultures. We envision that our approach will improve the efficiency of early-stage drug testing by:

  1. reconciling observations on cellular drug response with existing knowledge on metabolic pathways;
  2. identifying possible metabolic derivatives;
  3. quantifying metabolic burdens;
  4. estimating likelihoods of drug-drug interactions through shared metabolic pathways; and
  5. establishing predictive indices of metabolite markers for toxicity.