Chapter 6 Metabolite identification by lc-ms: applications in drug discovery and development

Abstract

Publisher Summary This chapter suggests that attention should be paid to the disposition characteristics of a drug candidate early on. This information sheds light on the absorption, distribution, metabolism and excretion (ADME) of potential drugs. These studies are performed (1) to support the selection of more efficacious and safer drugs for development, (2) to help understand pharmacological and toxicological observations, and (3) to determine dose levels and dose regimens. Currently, a wide variety of in vitro and in vivo screens are in place to obtain valuable information about ADME parameters for lead candidates. The in vitro studies include (1) metabolic stability in liver microsomes, hepatocytes or with recombinant cytochrome P450 enzymes, (b) metabolite formation in liver microsomes, hepatocytes or with recombinant cytochrome P450 enzymes, (3) absorption/transport studies in Caco-2 cells or cell lines over expressing various transporters, (4) cytochrome P450 inhibition, (5) cytochrome P450 induction, (6) plasma protein binding, and (7) red blood cell partitioning. The in vivo studies include (1) pharmacokinetic studies via various routes of administration (oral, intravenous, subcutaneous, etc.), (2) tissue distribution (e.g., brain penetration) and (3) metabolite identification in various biological fluids (plasma, bile, urine, etc.). It has been shown that many of these studies benefit from analysis by liquid chromatography interfaced with mass spectrometry (LC-MS).