Present and future in vitro approaches for drug metabolism.
The 1980s through 1990s witnessed the widespread incorporation of in vitro absorption, distribution, metabolism, and excretion (ADME) approaches into drug development by drug companies. This has been exemplified by the integration of the basic science of cytochrome P450s (CYPs) into most drug metabolism departments so that information on the metabolic pathways of drugs and drug-drug interactions (DDIs) is no longer an academic exercise, but essential for regulatory submission. This has come about due to the application of a variety of new technologies and in vitro models. For example, subcellular fractions have been widely used in metabolism studies since the 1960s. The last two decades has seen the increased use of hepatocytes as the reproducibility of cell isolations improved. The 1990s saw the rejuvenation of liver slices (as new slicers were developed) and the utilization of cDNA expressed enzymes as these technologies matured. In addition, there has been considerable interest in extrapolating in vitro data to in vivo for parameters such as absorption, clearance and DDIs. The current philosophy of drug development is moving to a 'fail early--fail cheaply' paradigm. Therefore, in vitro ADME approaches are being applied to drug candidates earlier in development since they are essential for identifying compounds likely to present ADME challenges in the latter stages of drug development. These in vitro tools are also being used earlier in lead optimization biology, in parallel with approaches for optimizing target structure activity relationships, as well as identification of DDI and the involvement of metabolic pathways that demonstrate genetic polymorphisms. This would suggest that the line between discovery and development drug metabolism has blurred. In vitro approaches to ADME are increasingly being linked with high-throughput automation and analysis. Further, if we think of perhaps the fastest available way to screen for successful drugs with optimal ADME characteristics, then we arrive at predictive computational algorithms, which are only now being generated and validated in parallel with in vitro and in vivo methods. In addition, as we increase the number of ADME parameters determined early, the overall amount of data generated for both discovery and development will increase. This will present challenges for the efficient and fast interpretation of such data, as well as incorporation and communication to chemistry, biology, and clinical colleagues. This review will focus on and assess the nature of present in vitro metabolism approaches and indicate how they are likely to develop in the future.
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Drop Code 0730, Indianapolis, IN 46285, USA. ekins_sean@lilly.com
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Ekins
B J
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Ring
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Grace
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McRobie-Belle
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Wrighton
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004345:Drug Industry; D004347:Drug Interactions; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
D004364:Pharmaceutical Preparations; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System