Seite - (000097) - in Biomedical Chemistry: Current Trends and Developments

– Speed: the experimental procedure must be fast enough to keep pace with the input rate of new compounds from chemistry; – Robustness: the experimental procedure must be applicable to a wide variety of chemical structures; – Accuracy and reproducibility: any screening procedure has an inevitable characteristic error rate, because it is usually necessary to sacrifice some accuracy or precision to achieve the desired speed. Thus, when a large number of compounds is carried through a particular screen model, some of the compounds will be classified incorrectly. False positives are tolerable, but false negatives may be lost forever if the failure eliminates them from further testing. It is also essential to regularly validate the in vitro models against in vivo data to ensure that decisions based on in vitro results are sufficiently predictive (Burton, 2010). Once exhibiting these characteristics, in vitro assays contribute to understanding the underlying mechanisms of drug absorption and disposition, which are invaluable to establishing structure-activity relationships to guide subsequent chemical synthesis of new drugs, avoiding potential obstacles in drug development. It is also important to highlight that in vitro data are in current practice recognized as good predictors of in vivo end-points. Even the Food and Drug Administration (FDA) accepts the importance of in vitro data, as it can inclusively avoid certain clinical studies (FDA, 2000, 2003, 2006). For instance, since a negative result in CYP induction for in vitro human-based studies using primary hepatocyte cultures always seems to lead to a negative induction in human clinical studies, FDA typically waives clinical DDI studies if the drug candidate is tested as negative in a human in vitro CYP induction study. However, the relative simplicity of in vitro systems for studying ADME/pharmacokinetics in comparison to real in vivo drug behavior means that absolute correlations between in vitro and in vivo findings are often difficult to establish routinely, particularly for humans. For this reason, in vitro screens are frequently viewed as a means to rank compounds for further study rather than for outright rejection, so the in vivo pharmacokinetic studies performed in animals during lead