Seite - (000098) - in Biomedical Chemistry: Current Trends and Developments

characterization remain crucial after in vitro evaluation. Without requiring full pharmacokinetic characterization, the in vivo studies performed at this stage ensure that lead compounds have appropriate pharmacokinetic properties to be evaluated in non-clinical pharmacology and safety studies (Table 2.1.1). In fact, when combined with in vitro results, they quickly assess the bioavailability of a compound, giving a good indication of the suitability for advancement to pre-clinical and clinical trials. The current trend is to use rodents (mice and rats) as first animal species to test drug exposure because they are less expensive and require smaller amount of test compound. These in vivo pharmacokinetic studies in rodents include single oral and intravenous pharmacokinetic studies and provide information such as drug oral bioavailability, distribution, clearance and duration of exposure for a drug and its metabolites. Thus, they can help to identify some limitations of a new chemical series regarding their ADME characteristics, such as low absorption or high clearance, leading to undesirable pharmacokinetic profiles. Subsequently, in vitro models such as Caco-2 can be used to optimize absorption of compounds from the same chemical series. The microsomal stability assay can also be applied to select more stable compounds. Although a continuous demand for in vivo pharmacokinetic studies remains at discovery stages, most of these studies are still conducted in a traditional, low-throughput manner in many pharmaceutical companies. Furthermore, compound quantities as well as practical and ethical issues preclude in vivo studies performed at a sufficient rate to investigate the high number of new drug candidates (Balani, 2005). Conventional pharmacokinetic studies include the intravenous and oral administration of each compound to groups of 6−8 animals with blood samples taken at 6−12 different points of time (Alves, 2008), requiring a high number of animals, time and intensive bioanalysis. Consequently, in order to make timely and meaningful contributions in early discovery programs, in vivo pharmacokinetic analysis has been efficiently modified and accomplished through recent strategies such as pooling of plasma samples and fewer sampling time points per study, reducing the number of samples analyzed per each compound (Table 2.1.3). Interestingly, similar pooling strategies have also been applied in order