Editorial[Hot Topic:Emerging Technologies for the Study of Drug Metabolism and Pharmacokinetics(Guest Editor:Yunsheng Hsieh)]

Improvement in research and development (R&D) productivity via leveraging the probability of technical success to efficiently bring the medicine to the market is a determining factor in maintaining a growing and sustainable pharmaceutical industry. The modern technology advance in drug metabolism and pharmacokinetics (DMPK) plays a key role in the drug discovery and development paradigms in selecting therapeutic drug candidates with better drug-like properties which in turn contribute to productivity growth. This special issue of Current Drug Discovery Technologies focuses on the emerging techniques in DMPK and acknowledges the efforts from contributors in making this issue possible. Benjamin B, Barman TK, Chaira T and Paliwal JK at the Department of Drug Metabolism & Pharmacokinetics, Ranbaxy Research Laboratories, proposed various physiological-pharmacokinetic-based models addressing absorption, tissue distribution and clearance via integration of the individual compound property to physiological properties to predict drug-like behavior. These prediction models should be able to provide a new direction of application for lead optimization process to avoid the need for performing a larger number of in vitro experiments with new chemical entities. Knowledge of the concentrations of the administrated drug candidates to induce an oxidative stress response that disrupts cell or tissue function will definitely help in the assessment of the safety window and potential liability upon co-administration with other components. Vickers AEM, Fisher RL and Sinclair JR from Drug Safety Evaluation, Allergan Inc., describe that human liver slices can be successfully used to investigate compound induced pathways of oxidative stress, which can be augmented in the presence of reduced glutathione (GSH) levels as an example. The authors demonstrate that generation of a stressed model via modulation of the GSH levels with both L-buthionine-S-sulfoximine (BSO) or acetaminophen (APAP) reflected the consequences of a poor liver GSH status, as well as human variability and the extent of response evident amongst the human donor livers. Valerio LG and Long A from Center for Drug Evaluation and Research, U.S. Food and Drug Administration and Lhasa Limited, respectively, present the use of a commercial software program to perform predictions in silico on seventeen hepatotoxic drugs for determining human-specific drug metabolites which might lead to chronic toxicity and cause potentially serious implications for clinical drug-drug interactions. The authors suggest that the proposed computational tools help support not only the development of therapeutics but also the safety assessment in identifying drug metabolites early to protect patients prior to initiating clinical studies. The primary site responsible for drug metabolism is normally the liver. So, the liver-derived in vitro systems such as slices, microsomes, S9 fractions, and hepatocytes are generally considered as an effective model for predictions of metabolic stability, enzyme induction, hepato-biliary transport, and hepatotoxicity for new chemical entities during lead optimization processes. Sahi J, Grepper S and Smith C from ADME/Tox Division of Life Technologies review traditional and newer in vitro approaches such as siRNA using primary hepatocytes to extrapolate clinical hepatic metabolism, transport and toxicity. Transporters are responsible to translocate substrates such as drugs against a concentration gradient across biological membranes which have been demonstrated to have an important role in controlling drug disposition and in the protection from toxic compounds. Inhibition and/or induction of transporter and drug metabolism enzymes may lead to drug-drug interaction. Lu C, Liao M, Cohen L and Xia CQ from Drug Metabolism and Pharmacokinetics department of Millennium Pharmaceuticals, Inc. assesses emerging in vitro methods with drug-drug interaction models for evaluating CYP450 and transporter-mediated issues in this review. Higher throughput bioanalytical methods for the simultaneous analysis of drug components and their metabolites with different chemical properties in complex biological samples are essential for supporting various drug discovery experiments. Hsieh Y at Drug Metabolism and Pharmacokinetics department of Merck Research Laboratories reviews hyphenation of hydrophilic interaction liquid chromatography (HILIC) with tandem mass spectrometry (MS/MS) techniques, which cover a wider range of pharmaceutical compounds in support of drug research as compared with traditional reversed-phase HPLCMS/ MS methods. It was concluded that any improvement in the design of HILIC columns and the instrumentation for MS detection should enhance the chance of success in extending the applications range of HILIC-MS/MS assays.