Drug Bioavailability

Drug Bioavailability In order to reach its intended site of action, the drug molecules in every pill that we swallow must first be absorbed, transported via the bloodstream and evade various mechanisms that eliminate drugs from the body. Those drug properties that determine, for example, its stability in the gut or its ease of uptake into the bloodstream, are therefore of central importance in drug development. In fact, many potentially useful drugs fail because of insufficient availability at the biological target site. This second edition of the gold standard for industrial research is thoroughly revised in line with current trends in the field, with all contributions extensively updated or rewritten. No other publication offers the same level of treatment on this crucial topic. In 22 chapters readers can benefit from the key working knowledge of today s leading pharmaceutical companies, including Pfizer, AstraZeneca, and Roche. Drug developers from industry and academia present all the factors governing drug bioavailability, complete with practical examples and real-life data. Part I focuses on solubility and gastrointestinal absorption, while the second discusses in vitro and in vivo measurements of physicochemical properties, such as membrane permeability and solubility. Part III is devoted to metabolism and excretory mechanisms. The much revised and expanded Part IV surveys current in silico approaches to predict drug properties needed to estimate the bioavailability of any new drug candidate. The final part shows new drug development approaches as well as delivery strategies. Indispensable for all those working in the pharmaceutical industry, pharmaceutical and medicinal chemists, and toxicologists.

21 Kapitel, durchgesehen und aktualisiert: In diesem neu aufgelegten Standardwerk erklären Wirkstoffforscher aus dem akademischen und industriellen Umfeld alle Faktoren, die die Bioverfügbarkeit von Wirkstoffen beeinflussen. Teil 1 konzentriert sich auf die Messung physikalischer Eigenschaften (in vivo und in vitro), Teil 2 diskutiert Löslichkeit und gastrointestinale Absorption, Teil 3 widmet sich Fragen des Metabolismus und der Exkretion. Der besonders intensiv überarbeitete Teil 4 geht auf moderne Computermodelle zur Abschätzung der Bioverfügbarkeit potenzieller Wirksubstanzen ein. Der letzte Teil beschäftigt sich mit der Verbesserung der Bioverfügbarkeit durch maßgeschneiderte Syntheseprozesse. -- Mit Beiträgen von Wissenschaftlern führender Pharmaunternehmen wie Pfizer, AstraZeneca und Roche!

IntroductionPart I. Physicochemical Aspects of Drug Dissolution and SolubilityAqueous Solubility in Discovery Chemistry, DMPK and Biological AssaysGastrointestinal Dissolution and Absorption of Class II DrugsIn Silico Prediction of Aqueous SolubilityPart II. Physicochemical and Biological Studies of Membrane Permeability and Oral AbsorptionPhysico-chemical Approaches to Drug AbsorptionHigh-throughput Measurement of Physicochemical Properties (pKa, solubility, log D, permeability)Cell Cultures for Permeability Assessment in Drug DiscoveryUse of Animals for the Determination of Absorption and BioavailabilityIn vivo Permeability Studies in the GI Tract of HumansPart III Role of Transporters and Metabolism in Oral AbsorptionTransporters in the GI TractHepatic Drug TransportThe Importance of Gut Wall Metabolism in Determining Drug BioavailabilityModified Cell Lines to Assess Active Transport and Metabolism during AbsorptionPart IV Computational Approaches to Drug Absorption and BioavailabilityCalculated Molecular Properties and Multivariate Statistical AnalysisComputational Absorption PredictionIn Silico Prediction of BioavailabilitySimulation of Absorption, Metabolism, and BioavailabilityP-Glycoprotein Structure-Activity RelationshipsPart V Drug Development IssuesApplication of the Biopharmaceutical Classification System Now and in the FutureProdrugsModern Delivery Strategies: Physiological Considerations for Orally Administered MedicationsThe Promise of Nanotechnology in Drug Delivery