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 integr ation of the basic science of cytochrome P450s (CYPs) into most drug metabo lism departments so that information on the metabolic pathways of drugs and drug-drug interactions (DDIs) is no longer an academic exercise, but essen tial for regulatory submission. This has come about due to the application of a variety of new technologies and in vitro models. For example, subcellu lar fractions have been widely used in metabolism studies since the 1960s. The last two decades has seen the increased use of hepatocytes as the repro ducibility of cell isolations improved. The 1990s saw the rejuvenation of l iver slices (as new slicers were developed) and the utilization of cDNA exp ressed enzymes as these technologies matured. In addition, there has been c onsiderable interest in extrapolating in vitro data to in vivo for paramete rs such as absorption, clearance and DDIs. The current philosophy of drug d evelopment is moving to a 'fail early-fail cheaply' paradigm. Therefore, in vitro ADME approaches are being applied to drug candidates earlier in deve lopment since they are essential for identifying compounds likely to presen t 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 th at demonstrate genetic polymorphisms. This would suggest that the line betw een discovery and development drug metabolism has blurred. In vitro approac hes to ADME are increasingly being linked with high-throughput automation a nd analysis. Further, if we think of perhaps the fastest available way to s creen for successful drugs with optimal ADME characteristics, then we arriv e at predictive computational algorithms, which are only now being generate d 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. (C) 2001 Elsevier Science Inc. All rights reserve d.