Drug Metabolism & Pharmacokinetics in Drug Discovery : A Primer for Bioanalytical Chemists , Part I

pressures of competition have caused enormous changes in the drug discovery process. Progress in molecular biology and the Human Genome Project has contributed to the remarkable advances made in identification of new therapeutic targets. The drug discovery process is rapidly evolving due to the technological developments in target identification along with automation of combinatorial synthesis and high throughput screening (HTS). In light of these advances, improving efficiency in the optimization of desired pharmacological activity in humans while decreasing the reliance on animal studies has become a challenge. New chemical entities (NCEs) enter the drug discovery pipeline through combinatorial synthesis and rational drug design where information about the target of action is used to design the lead compound. HTS helps the identification of the leads that provide the required effect at high concentrations. In the secondary screening stage physicochemical properties such as solubility, liphophilicity and stability are determined by measuring the octanolwater partition coefficient and pKa. These measurements are useful in predicting the protein binding, tissue distribution and absorption in the gastrointestinal tract (1). The selected leads are further screened using in vitro tests during lead optimization. The goal of lead optimization is to select compounds with required biological activity in humans. Relevant pharmacokinetic parameters such as tissue penetration, stability, intestinal absorption, metabolism, and elimination are obtained using in vitro systems. These in vitro systems include microsomes, hepatocytes or tissue slices for metabolite identification and evaluation of metabolic pathways and rates, and caco-2 cell lines for evaluating transcellular absorption. Cytotoxicity data can be obtained by using organ-specific cell lines. Knowledge of the toxic potential of these early leads and their possible metabolites is essential for successful drug discovery. Most drug candidates fail at this stage and only a few will be judged sufficiently safe and efficacious to proceed further into development. Both in vitro Drug Metabolism & Pharmacokinetics in Drug Discovery: A Primer for Bioanalytical Chemists, Part I