Talk:Samer Aljundi Chem430 F16

- ADME is an abbreviation in pharmacokinetics and pharmacology for "absorption, distribution, metabolism, and excretion," and describes the disposition of apharmaceutical compound within an organism. The four criteria all influence the drug levels and kinetics of drug exposure to the tissues and hence influence the performance and pharmacological activity of the compound as a drug. (https://en.wikipedia.org/wiki/ADME)

- ADME Studies - Preclinical ADME studies are designed to investigate the absorption, distribution, metabolism and excretion of novel pharmaceuticals to support lead candidate selection, preclinical testing and clinical development programs. Charles River offers custom-designed ADME studies in multiple species using cold or radiolabeled test materials administered by a variety of routes. - Our experienced scientists routinely conduct mass balance and tissue distribution studies to determine tissue half-life, clearance rates and potential sites of toxicity after systemic exposure. These studies are all managed using the DEBRA® Windows LIMS System to provide full electronic data collection and evaluation. We can arrange and manage custom radiosynthesis on your behalf and are able to undertake re-purification and radiodilution of radiolabeled test materials if required. (http://www.criver.com/products-services/safety-assessment/toxicology/drug-metabolism-pharmacokinetics/adme)

- Discovering a new drug is a complex but sequential process from discovery to preclinical development, followed with clinical drug development. It has been estimated that ∼ 87% of the phase III failures are accounted for either due to lack of efficacy (66%) or due to safety issues (21%). Majority of these failures are for compounds targeted for novel mechanisms of actions with unmet medical need, in particular, oncology and neurodegenerative disorders. Some of the reasons for these failures can be attributed to lack of appropriate preclinical animal models, biomarkers/surrogate markers, and effective pharmacokinetic (PK)–pharmacodynamic (PD) evaluation during early drug discovery. Translational research that integrates computer-aided drug design (CADD), PK, PD, drug metabolism (DM), and drug transport along with biomarkers and humanized animal models are instrumental in making informed decisions from early drug discovery through clinical development. The ability to correlate drug effect through modeling and simulations starts from early drug discovery and preclinical evaluation, including use of novel biomarkers. Such models validate the PK and PD relationships and provide a basis for their applications and guide the Phase I through Phase III clinical trials more effectively, minimizing the late stage failures. Thus, PK–PD evaluation has become an integral part of drug discovery and provides valuable insights to aid in optimizing the next steps for drug development. This chapter is focused on translational drug discovery research with particular emphasis on selective utilization of CADD; absorption, distribution, metabolism, and excretion; toxicology; PK; and PD evaluations, which identify potential liabilities early so as to minimize late-stage failures during drug development. This chapter also provides a brief overview on means and measures that can be adopted to integrate early drug discovery research along with efficacy and safety biomarkers for meaningful transition to drug development. (http://onlinelibrary.wiley.com/doi/10.1002/9780470921920.edm038/abstract)

- Abstract - There is an increasing recognition within the pharmaceutical industry of the importance of the ADME studies in drug registration. Consequently, there has been a drive in recent times to conduct the ADME studies as early as possible in the development programme. There are, however, regulatory barriers, particularly in the administration of radiotracers to human volunteers, which place limitations on the timing of the ADME studies. Accelerator mass spectrometry (AMS), a technology new to the pharmaceutical industry, is an ultrasensitive technique for measuring tracers such as 14C. Using AMS, it is possible to lower the radioactive dose administered to humans to a point where many regulatory authorities consider it insignificant. With the removal of the regulatory hurdles, ADME data can be obtained much earlier in the development process. Tracers such as 14C can be administered in minute amounts in the first in man studies (Phase I), or even in a preregulatory study known as microdosing (or human Phase 0). AMS also enables other studies such as absolute bioavailability to be conducted earlier if required. (http://www.tandfonline.com/doi/abs/10.1517/17425255.1.1.23)

- An understanding of the functional roles of proteins, for example, in drug absorption, distribution, metabolism, elimination, toxicity, and efficacy (ADMET/efficacy), is important for drug discovery and development. Equally, detailed information about protein expression is required. Recently, a new protein quantification method, called quantitative targeted absolute proteomics (QTAP), has been developed on the basis of separation and identification of protein digests by liquid chromatography–linked tandem mass spectrometry with multiple reaction monitoring. Target peptides for quantification are selected only from sequence information, so time-consuming procedures such as antibody preparation and protein purification are unnecessary. In this review, we introduce the technical features of QTAP and summarize its advantages with reference to recently reported results. These include the evaluation of species differences of blood–brain barrier protein levels among human, monkey, and mouse. The high selectivity of QTAP and its ability to quantify multiple proteins simultaneously make it possible to determine the absolute expression levels of many proteins in tissues and cells in both physiological and disease states. Knowledge of absolute expression amounts, together with data on intrinsic protein activity, allows us to reconstruct in vivo protein function, and this should be an efficient strategy to predict ADMET/efficacy of drug candidates in humans in various disease states. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3547–3559, 2011 (http://onlinelibrary.wiley.com/doi/10.1002/jps.22612/full)