ABSTRACT
The process of drug discovery and development involves many stages including drug design, in vitro studies of drug candidate metabolism, evaluation of potential toxicity of drugs and their metabolites, and determination of protein binding and in vivo pharmacokinetics (PK) with animal models. Most of these steps are very challenging because in vitro drug activity cannot always be extrapolated easily to its in vivo activity and because the limited availability of a new compound restricts in vivo studies to one or two animal species [1]. Although intraspecies variations in absorption, distribution, metabolism, and elimination (ADME) of drugs may result in different pharmacokinetic proles in humans than expected from animal data, animal studies remain a critical step in the process of drug development. However, there is a low throughput of in vivo PK screening, a limited number of methods feasible for in vivo studies, and strict regulations that force pharmaceutical companies to minimize the number of animals used for experimentation. These factors lead to the continuous introduction of new strategies to address these issues [2]. Finally, when a drug is approved for preclinical and clinical uses in human subjects, the pharmacological and pharmacokinetic properties of the drug must be veried. Polymorphism of enzymes, clinical condition of the patient, coexisting diseases, and multidrug therapy may all signicantly affect the predicted concentration of the drug; thus, dosing regimen verication and therapeutic drug monitoring are required. Recently, the monitoring of drug-induced metabolome prole changes presented the opportunity to personalize pharmacotherapy and increase its effectiveness.
