Correct dosing in pharmacotherapeutics is based on the idea that too much of a drug will cause toxicity, while too little will result in failure to elicit the desired response. A major factor in the ability of a patient to handle any dose of a drug is the capacity to metabolize and eliminate that drug from the body. For the vast majority of drugs, the liver plays a key role in determining the rate at which drugs are eliminated. First, drugs must be taken up across the cell membrane into hepatocytes by uptake transporters. Once inside the hepatocyte, biotransformation enzymes metabolize and conjugate the drug to a more water-soluble compound, the distribution of which is more easily controlled. These water-soluble metabolites are then transported out of the hepatocyte by additional drug transporters either into bile for elimination, or back into the blood. More than 2 million severe adverse drug reactions occur in the US each year and often result from interindividual variation in the ability to metabolize and eliminate drugs. This number does not include medical errors, but rather circumstances where an individual is unable to handle the standard dose of the correctly prescribed drug. Although genetics plays an important role, the greatest source of variation comes from other environmental factors such as disease states. Nonalcoholicfatty liver disease (NAFLD) is a chronic condition that comprises a spectrum of histopathologies that range from simple steatosis to the more severe steatohepatitis. Specifically, nonalcoholic steatohepatitis (NASH) has become one of the leading causes for liver transplantation in the United States, and thus clearly become a considerable burden to the U.S. healthcare system. It is not known whether the capacity of the liver to metabolize and excrete drugs is altered in patients with NASH. Because the liver plays such a critical role in drug metabolism and disposition, any disease state that disrupts or modifies these functions will alter the fate of a given drug within the body. It is therefore very likely that the ability of the liver to metabolize and excrete clinically relevant drugs is compromised in NASH patients.

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

TRANSPORTERS AND DRUG-METABOLIZING ENZYMES IN DRUG TOXICITY Explore up-to-date coverage on the interaction between drug metabolism enzymes, transporters, and drug toxicity with this leading resources Transporters and Drug-Metabolizing Enzymes in Drug Toxicity delivers a comprehensive and updated review of the relationship between drug metabolism, transporters, and toxicity, providing insights into a major challenge in drug development – accurate assessment of human drug toxicity. Combining two disciplines frequently considered independently of one another, the book combines drug metabolism and toxicology with a focus on the role of biotransformation on drug toxicity and as a major factor for species and individual differences. Mechanism and species differences in drug metabolizing enzymes and transporters are discussed, as are the methods used to investigate the role of drug metabolizing enzymes and transporters in drug toxicity. Finally, the distinguished authors describe promising new experimental approaches to accurately assessing human drug toxicity via the consideration of human-specific drug metabolism in toxicity assays. In addition to topics as diverse as extended clearance models, experimental approaches for the estimation of DILI potential of drug candidates and roles of transporters in renal drug toxicity, readers will also enjoy the inclusion of such subjects as: A thorough overview of and introduction to drug metabolism and transporters and drug toxicity An exploration of drug metabolism enzymes and transporter activities as risk factors of marketed drugs associated with drug-induced fatalities A discussion of human-based in vitro experimental models for the evaluation of metabolism-dependent drug toxicity A treatment of mechanism-based experimental models for the evaluation of BSEP inhibition and DILI An examination of transporters and cochlea toxicity Perfect for scientists, students, and practitioners with interests in metabolism, toxicology, and drug development in the pharmaceutical industry, Transporters and Drug-Metabolizing Enzymes in Drug Toxicity will also earn a place in the libraries of medicinal chemists, pharmacologists, biochemists, toxicologists, and regulators in the pharmaceutical and health industries.

Inter-individual variability in drug response is a significant clinical concern and may lead to the development of adverse drug reactions, which are currently a top-ten cause of death in the United States. Recently, the manifestation of disease, which may alter normal physiological function, has gained increased attention for its role as a contributing factor in the development of inter-individual responses to drugs. One such disease, known as nonalcoholic fatty liver disease (NAFLD), is the most common chronic liver disease in Western society and represents a spectrum of clinical morbidities that range from the usually benign simple fatty liver to the more advanced nonalcoholic steatohepatitis (NASH). Prior investigations have identified liver-specific alterations in xenobiotic transporter and metabolizing enzymes in NASH, which lead to the functional disruption of drug disposition. To identify a useful model(s) that is representative of hepatic transporter expression profiles in humans with NASH, gene and protein expression profiles of liver membrane transporters were assayed across several commonly used experimental rodent models of the disease. NASH models that were representative of the human condition developed global, adaptive changes in transporter regulation in the liver, which was not present in models that failed to recapitulate human profiles. Specifically, decreased expression of hepatic uptake transporters was coupled with an induction of efflux transporters, which may serve as a hepatoprotective response by limiting hepatic exposure to potentially harmful substances during times of tissue stress. To link a possible molecular mechanism for these hepatic adaptations in NASH, the role of the oxidative stress-activated transcription factor, Nrf2, was investigated. A functional Nrf2 regulatory element was identified within the eighth intron of the human ABCC3 transporter gene, implicating Nrf2 activation in NASH as a contributor to the coordinated induction of hepatic efflux transporters in the disease. To further clarify the effects of NASH on renal membrane transporter regulation, a thorough analysis of gene and protein expression was conducted with the validated rodent models used previously. Following the manifestation of disease, a global induction of renal efflux was observed, suggesting a compensatory, coordinated response of membrane transporters in the kidney upon disease induction. The functional consequences of liver and kidney xenobiotic transporter dysregulation was shown to disrupt the disposition of the environmental toxicant, arsenic. Specifically, NASH results in increased excretion of arsenic into urine as well as altered hepatic and renal exposure. These findings are associated with hepatic and renal transporter dysregulation and demonstrate for the first time that NASH alters the disposition of environmental toxicants. In summary, these studies contribute novel findings that identify liver and kidney-specific adaptations in disease that may contribute to global alterations in xenobiotic disposition thereby increasing the likelihood of developing adverse drug reactions in patients with NASH.

Dr. Rustgi has assembled the leading experts in the management of Heptatitis B to present the current treatment and clinical course for diagnosis and management of the disease. Articles are devoted to: Drug metabolism in the liver; Mechanism of Liver Damage including the RUCAM scale; Drug-induced acute liver failure; Epidemiology and genetic risk factors; Adverse drug reactions: type A (intrinsic or pharmacological) or type B (idiosyncratic); Pathology of injury including phenotypes; The clinical course of drug-induced liver disease; Environmental factors of drug hepatotoxicity; Newer agents in drug hepatotoxicity; Drug hepatotoxicity: herbal products; Drug hepatotoxicity: models including “human on a chip and zebrafish; Acute and chronic liver failure from drugs: impact on the kidney; and Management of acute hepatotoxicity including medical agents and liver support systems. Readers will come away with the cutting edge science behind the latest innovations in the treatment of Hepatitis B.

It is increasingly recognized that various transporter proteins are expressed throughout the body and determine absorption, tissue distribution, biliary and renal elimination of endogenous compounds and drugs and drug effects. This book will give an overview on the transporter families which are most important for drug therapy. Most chapters will focus on one transporter family highlighting tissue expression, substrates, inhibitors, knock-out mouse models and clinical studies.

This book provides with a comprehensive overview of the role of drug transporters in drug disposition and efficacy/toxicity, as well as drug-drug interactions and recent advances in the field. Transporters are known determinants of drug disposition and efficacy/toxicity. In general, they are divided into solute carrier (SLC) and ATP binding cassette (ABC) families, and are located along cell membranes, where they mediate drug uptake into cells and export out of cells. Drug transporters are essential in maintaining cell homeostasis, and their gene mutations may cause or contribute to severe human genetic disorders, such as cystic fibrosis, neurological disease, retinal degeneration, anemia, and cholesterol and bile transport defects. Conversely, some diseases may also alter transporter functions and expressions, in turn aggravating disease process. Further, since over-expression of some ABC transporters is a potential contributor to multidrug-resistance (MDR), the book presents a number of strategies to overcome MDR, including ABC transporter inhibitors and applying epigenetic methods to modulate transporter expressions and functions. This book is useful for graduate students and professionals who are looking to refresh or expand their knowledge of this exciting field.