The conduct of drug metabolism studies considered good practice (I): analytical systems and in vivo studies.

This review serial outlines practical and scientifically-based approaches to conducting contemporary drug metabolism studies considered good practice for drug development and regulatory filing. The present part addresses analytical methods used in the drug metabolism studies and evaluates advantages and disadvantages of these methods as well as the related sample preparations. The methods described here cover from conventional radioactive labeling of drugs, which includes selection of a proper radioisotope, its labeling position, and modern radio-pharmacokinetics employed in microdosing by using a radionuclide to visualize drug distribution in vivo, to currently widely-used liquid chromatography (LC) in conjunction with mass spectrometry (MS), tandem mass spectrometry (MS/MS), and nuclear magnetic resonance (NMR) for quantitative detection of metabolites and characterization of their structures. Although the analytical tools have progressed sufficiently to allow determination of metabolites, proper in vitro models and in vivo studies have to be carefully designed in order to understand drug metabolism. Points for consideration when conducting in vivo drug metabolism studies include interspecies differences in systemic exposure and metabolism pathways, identification of the major metabolites and unique human metabolites that become the regulatory focus, local metabolism in addition to liver metabolism, time points for sampling, and synthesis of the authentic metabolites to confirm their formation. The next part of this serial article will focus on in vitro drug metabolism studies.