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The book provides an exhaustive, authoritative and updated review on the interindividual variability in drug metabolism in humans. Four chapters address the general background: genetic factors causing variability, interethnic variability, environmental factors and developing and ageing as sources of variability. Six chapters address variability of drug metabolism in vivo: variability of psychotropic drugs, antiepileptic drugs, the dopamine precursor levodopa, cardiovascular active drugs and anti HIV drugs. Seven chapters address the interindividual variability of the main drug metabolizing enzymes: CYP-450s, acetyltransferases, glucuronosyl transferase, methyl transferases, sulfotransferases and glutathione transferases in human liver and extrahepatic tissues. A separate chapter discusses the prediction of drug interaction. Comprehensive in coverage, and with contributions from the leading international experts, this book is essential reading for researchers from both academia and the pharmaceutical industry. Advanced undergraduates and postgraduates in pharmacology, clinical pharmacology, toxicology, biochemistry and epidemiology who are interested in drug metabolism will also find this an indispensable resource.
UGT2B17 is an androgen- and drug-conjugating enzyme with a remarkably high interindividual variability in its hepatic protein expression. Testosterone is one of its main endogenous substrates, and various clinical associations between UGT2B17 and testosterone-related and other pathophysiological outcomes have been reported, along with associations with drug and xenobiotic disposition. UGT2B17 also exhibits relatively high and variable intestinal abundance, compared to the liver, both in absolute abundance and relative to other UGT isoforms, which brings in concern for first pass metabolism and differential drug-drug interactions. Multiple factors, including a common copy number variation (CNV), sex, age, and certain SNPs, contribute to UGT2B17 tissue abundance variability, but only account for a small portion of that variability. Unexplained interindividual differences in UGT2B17 tissue abundance, along with UGT2B17's unique ontogeny, highlights the need for a phenotypic biomarker to assess in vivo UGT2B17 activity. This dissertation project focuses on characterizing interindividual variability and differential tissue abundance of UGT2B17. Chapter 2 explores UGT2B17's role in first pass metabolism of testosterone in human in vitro models for the small intestine and liver and explores its role in the disposition of orally administered testosterone. Findings confirm that UGT2B17 drives testosterone glucuronide (TG) formation in liver and intestine, and the higher intestinal abundance may explain oral testosterone's high and variable first pass metabolism and low bioavailability. In Chapter 3, urinary TG normalized with androsterone glucuronide (TG/AG) is identified as a potential urinary biomarker for UGT2B17 and validated in longitudinal urine samples from 63 pediatric subjects. Significant associations between TG/AG and sex, age, and UGT2B17 CNV were found. Chapter 4 investigates regional enzyme abundance of UGT2B17 and non-CYP enzymes in cryopreserved human intestinal mucosa (CHIM), corroborates proteomic findings with activity assays, and proposes enterocyte marker proteins as normalizers to control for intestinal tissue heterogeneity. Non-CYP enzymes that were quantifiable were carboxylesterase 1 (CES1), CES2, UGT1A1, UGT1A3, UGT1A10, UGT2B7, UGT2B17, sulfotransferase 1A1 (SULT1A1), SULT1A3, SULT1B1, and SULT2A1. We also found good enzyme abundance-activity correlations, demonstrating that CHIMs are functionally active with respect to xenobiotic metabolism. This dissertation improves the understanding of UGT2B17's role in first pass drug metabolism and potential drug-drug interactions. It also establishes a promising phenotypic urinary biomarker for UGT2B17 for further applications in drug development and disease state associations.
Advances in the technology used in personalized medicine and increased applications for clinical use have created a need for this expansion and revision of Kewal K. Jain’s Textbook of Personalized Medicine. As the first definitive work on this topic, this book reviews the fundamentals and development of personalized medicine and subsequent adoptions of the concepts by the biopharmaceutical industry and the medical profession. It also discusses examples of applications in key therapeutic areas, as well as ethical and regulatory issues, providing a concise and comprehensive source of reference for those involved in healthcare management, planning and politics. Algorithms are included as a guide to those involved in the management of important diseases where decision-making is involved due to the multiple choices available. Textbook of Personalized Medicine, Second Edition will serve as a convenient source of information for physicians, scientists, decision makers in the biopharmaceutical and healthcare industries and interested members of the public.
The book provides an exhaustive, authoritative and updated review on the interindividual variability in drug metabolism in humans. Four chapters address the general background: genetic factors causing variability, interethnic variability, environmental factors and developing and ageing as sources of variability. Six chapters address variability of
Oral Drug Absorption, Second Edition thoroughly examines the special equipment and methods used to test whether drugs are released adequately when administered orally. The contributors discuss methods for accurately establishing and validating in vitro/in vivo correlations for both MR and IR formulations, as well as alternative approaches for MR an
Drug Metabolism in Diseases is a comprehensive reference devoted to the current state of research on the impact of various disease states on drug metabolism. The book contains valuable insights into mechanistic effects and examples of how to accurately predict drug metabolism during these different pathophysiological states. Each chapter clearly presents the effects of changes in drug metabolism and drug transporters on pharmacokinetics and disposition. This is a unique and useful approach for all those involved in drug discovery and development, and for clinicians and researchers in drug metabolism, pharmacology, and clinical pharmacology. Written and edited by leaders in drug metabolism from academia and industry Covers important topics, such as pharmacogenomics, drug metabolism in transplant patients, xenobiotic receptors, drug metabolism in geriatric and pediatric populations, and more Highlights topics of importance in drug discovery and development, and for safe and effective drug use in the clinic
Following its successful predecessor, this book covers the fundamentals, delivery routes and vehicles, and practical applications of drug delivery. In the 2nd edition, almost all chapters from the previous are retained and updated and several new chapters added to make a more complete resource and reference. • Helps readers understand progress in drug delivery research and applications • Updates and expands coverage to reflect advances in materials for delivery vehicles, drug delivery approaches, and therapeutics • Covers recent developments including transdermal and mucosal delivery, lymphatic system delivery, theranostics • Adds new chapters on nanoparticles, controlled drug release systems, theranostics, protein and peptide drugs, and biologics delivery
Chromatin Signaling and Neurological Disorders, Volume Seven, explores our current understanding of how chromatin signaling regulates access to genetic information, and how their aberrant regulation can contribute to neurological disorders. Researchers, students and clinicians will not only gain a strong grounding on the relationship between chromatin signaling and neurological disorders, but they'll also discover approaches to better interpret and employ new diagnostic studies and epigenetic-based therapies. A diverse range of chapters from international experts speaks to the basis of chromatin and epigenetic signaling pathways and specific chromatin signaling factors that regulate a range of diseases. In addition to the basic science of chromatin signaling factors, each disease-specific chapter speaks to the translational or clinical significance of recent findings, along with important implications for the development of epigenetics-based therapeutics. Common themes of translational significance are also identified across disease types, as well as the future potential of chromatin signaling research. Examines specific chromatin signaling factors that regulate spinal muscular atrophy, ulbospinal muscular atrophy, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, multiple sclerosis, Angelman syndrome, Rader-Willi syndrome, and more Contains chapter contributions from international experts who speak to the clinical significance of recent findings and the implications for the development of epigenetics-based therapeutics Provides researchers, students and clinicians with approaches to better interpret and employ new diagnostic studies for treating neurological disorders
The Institute of Medicine's (IOM's) Roundtable on Research and Development of Drugs, Biologics, and Medical Devices evolved from the Forum on Drug Development, which was established in 1986. Sponsor representatives and IOM determined the importance of maintaining a neutral setting for discussions regarding long-term and politically sensitive issues justified the need to revise and enhance past efforts. The new Roundtable is intended to be a mechanism by which a broad group of experts from the public* and private sectors can be convened to conduct a dialogue and exchange information related to the development of drugs, biologics, and medical devices. Members have expertise in clinical medicine, pediatrics, clinical pharmacology, health policy, health insurance, industrial management, and product development; and they represent interests that address all facets of public policy issues. From time to time, the Roundtable requests that a workshop be conducted for the purpose of exploring a specific topic in detail and obtaining the views of additional experts. The first workshop for the Roundtable was held on April 14 and 15, 1998, and was entitled Assuring Data Quality and Validity in Clinical Trials for Regulatory Decision Making. The summary on that workshop is available from IOM. This workshop summary covers the second workshop, which was held on May 24 and 25, 1999, and which was aimed at facilitating the development and proper use of drugs, biologics, and medical devices for infants and children. It explores the scientific underpinnings and clinical needs, as well as the regulatory, legal, and ethical issues, raised by this area of research and development.