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Integration of in vitro approaches to predict drug metabolism and interactions in man in development of pharmaceuticals

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Prediction of drug metabolism accelerates development of pharmaceuticals

In the research and development process for new drugs, detailed knowledge of the metabolic routes the drugs may follow is of great importance. The metabolism of drugs determines their pharmacokinetic behaviour and their interactions with other compounds. The objective of the current project has been the improvement of the in vitro methods for predicting the metabolic behaviour during drug research and development.

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Most of the time, drug metabolism is responsible for the inability to extrapolate on humans, a toxicology test performed on other species. Since it determines their pharmaceutical efficiency, a number of approaches have been followed for the prediction of drug metabolism. The current project has successfully identified a number of suitable tests and has developed an integrated approach for the prediction of the metabolism of drugs. Project partners have selected and characterised a number of enzyme-specific substrates and reagents like chemicals and antibodies. Systems with different levels of biological complexity were characterised and genetically manipulated to become more efficient. Finally a systematic comparison between these systems and with human in vitro data was made. The systems used; microsomes, liver slices, hepatocytes and recombinants were selected for their specificity, kinetic fidelity, stability and technical feasibility. Research has established that cultured hepatocytes and slices can provide a useful system for assessing the induction potential of drugs. It was also demonstrated that all systems are capable of short term studies of drug metabolism and that the application of several systems is necessary for a precise prediction of the metabolic interactions of a new drug. Project partners have the exclusive rights of the derived methodology and the proposed tests. The approach when applied to drug research will improve the design and execution of toxicity tests and facilitate early clinical trials. Furthermore costs of drug development will be reduced as will the number of animals for laboratory toxicity tests since now clinical studies can be targeted more on in vitro results.

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