TOXICITY AND DRUG TESTING pptx

TOXICITY AND DRUG TESTING Edited by William Acree Toxicity and Drug Testing Edited by William Acree Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2012 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. As for readers, this license allows users to download, copy and build upon published chapters even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. Notice Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book. Publishing Process Manager Molly Kaliman Technical Editor Teodora Smiljanic Cover Designer InTech Design Team First published February, 2012 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechweb.org Toxicity and Drug Testing, Edited by William Acree p. cm. ISBN 978-953-51-0004-1 Contents Preface IX Part 1 Drug Design 1 Chapter 1 Blood Brain Barrier Permeation 3 Abolghasem Jouyban and Somaieh Soltani Chapter 2 Diagnostic Accuracy and Interpretation of Urine Drug Testing for Pain Patients: An Evidence-Based Approach 25 Amadeo Pesce, Cameron West, Kathy Egan-City and William Clarke Chapter 3 Experimental and Computational Methods Pertaining to Surface Tension of Pharmaceuticals 47 Abolghasem Jouyban and Anahita Fathi-Azarbayjani Chapter 4 Multi-Well Engineered Heart Tissue for Drug Screening and Predictive Toxicology 71 Alexandra Eder, Arne Hansen and Thomas Eschenhagen Chapter 5 Prediction of Partition Coefficients and Permeability of Drug Molecules in Biological Systems with Abraham Model Solute Descriptors Derived from Measured Solubilities and Water-to-Organic Solvent Partition Coefficients 91 William E. Acree, Jr., Laura M. Grubbs and Michael H. Abraham Chapter 6 Variability of Plasma Methadone Concentration in Opiate Dependent Receiving Methadone: A Personalised Approach Towards Optimizing Dose 129 Nasir Mohamad, Nor Hidayah Abu Bakar, Tan Soo Choon, Sim Hann Liang, NIM Nazar, Ilya Irinaz Idrus and Rusli Ismail VI Contents Chapter 7 Drug Synergy – Mechanisms and Methods of Analysis 143 Hans-Georg Breitinger Chapter 8 Herbal Medicine in the Treatment of Malaria: Vernonia amygdalina: An Overview of Evidence and Pharmacology 167 Anoka A. Njan Chapter 9 Experimental and Computational Methods Pertaining to Drug Solubility 187 Abolghasem Jouyban and Mohammad A. A. Fakhree Part 2 Toxicity 219 Chapter 10 Toxic Effects of Cadmium on Crabs and Shrimps 221 Xianjiang Kang, Shumei Mu, Wenyan Li and Na Zhao Chapter 11 Paraquat, Between Apoptosis and Autophagy 237 Rosa A. González-Polo, José M. Bravo-San Pedro, Rubén Gómez-Sánchez, Elisa Pizarro-Estrella, Mireia Niso-Santano and José M. Fuentes Chapter 12 Prediction of Toxicity, Sensory Responses and Biological Responses with the Abraham Model 261 William E. Acree, Jr., Laura M. Grubbs and Michael H. Abraham Chapter 13 Mikania glomerata and M. laevigata: Clinical and Toxicological Advances 297 João Cleverson Gasparetto, Roberto Pontarolo, Thais M. Guimarães de Francisco and Francinete Ramos Campos Chapter 14 Evaluation of Drug Toxicity for DNA Vaccine Candidates Against Infectious Diseases: Hepatitis C as Experimental Model 321 Dania Bacardí, Karelia Cosme, José Suárez, Yalena Amador-Cañizares and Santiago Dueñas-Carrera Chapter 15 Aluminium Phosphide Poisoning 345 Babak Mostafazadeh Chapter 16 Application of a New Genotoxicity Test System with Human Hepatocyte Cell Lines to Improve the Risk Assessment in the Drug Development 361 Tsuneo Hashizume and Hiroaki Oda Contents VII Chapter 17 Genotoxic Impurities in Pharmaceuticals 387 Abolghasem Jouyban and Hamed Parsa Chapter 18 Measurement Uncertainty in Forensic Toxicology: Its Estimation, Reporting and Interpretation 415 Rod G. Gullberg Chapter 19 Toxicokinetics and Organ-Specific Toxicity 457 P.D. Ward Chapter 20 Environmental Toxicants Induced Male Reproductive Disorders: Identification and Mechanism of Action 473 Kuladip Jana and Parimal C. Sen Preface Book focuses on experimental in vivo and in vitro methods used to measure the ADMET properties (absorption, distribution, metabolism, excretion and toxicity) of potential drug candidates. Modern drug design also includes in silico computation methods to estimate ADMET properties, and several predictive methods are presented for drug solubility, blood-to-tissue partition coefficients, toxicity, nasal pungency and several other biological and sensory responses. One chapter is devoted to measurement uncertainty, bias and statistical treatment of experimental data. Analytical methods employed to identify and quantify genotoxic pharmaceutical impurities and drug metabolites are also described. Toxicity data from clinical studies are reported. Authors from several countries have contributed chapters detailing regulatory policies, pharmaceutical concerns and clinical practices in their respective countries. The open exchange of scientific results and ideas will hopefully lead to improved pharmaceutical products and a greater awareness of the vast toxicological issues that we all experience. Dr. William Acree University of North Texas, United States [...]... Anti cancer drugs, A broad range of drugs and xenobiotics (normally uncorticoids conjugated, cationic substances) Efflux Multi -drug resistance proteins Drugs and xenobiotics (normally conjugated, anionic substances) Breast cancer resistant proteins Drugs and xenobiotics (overlap Some anti cancer Drugs with P-glycoproteins and multidrug resistance proteins) Anti cancer and anti HIV Efflux Drugs Table... fractions directly 12 Toxicity and Drug Testing Fig 5 Different equilibria in brain 4.1.2 The importance of free drug measurement The free drug is responsible for pharmacokinetic and pharmacodynamic properties of drugs and relation between dose and response is correct when free drug supplies in target tissue get into account In this regard interstitial fluid and intra cellular fluid drug levels in brain... 2010) 8 Toxicity and Drug Testing Fig 4 Bulk phase and facilitated endocytosis 3.3 Active transport Hydrophilic drugs which cannot penetrate the brain through passive diffusion and lipophilic drugs which cannot penetrate the brain, in contrast of their suitable characteristics for BBB permeation are substrate for drug transporters of the BBB Also some compounds are substrates for transporters and at... compartments in the regulating of drugs and xenobiotics penetration to the brain has been discussed Working as a regulatory interface BBB is able to work as a physical and physiological barrier which prevents peripheral drugs to penetrate the brain and reduce 22 Toxicity and Drug Testing their CNS side effects This barrier activity causes some difficulties in CNS drug delivery and different measurement methods... cases and researchers are able to define different aspects of drug passage to the brain using these methods 10 Toxicity and Drug Testing Transporter name Substrates Organic anion transporting polypeptides Anionic amphipathic molecules Fexofenadine, Digoxin, with molecular weight greater Methotrexate than 450 Daltons and a high degree of albumin binding Organic anion transporters Anionic drugs and nucleotides... order to develop successful drug candidates for CNS disorders drug uptake mechanisms should be studied In the next section, these mechanisms are briefly reviewed Fig 2 Tight junctions and adherent junctions 6 Toxicity and Drug Testing 3 BBB permeation mechanisms Like other cellular membranes in the body, permeation through BBB can occur by passive diffusion, endocytosis and active transport (Diagram... linear Diagram 2 Brain drug testing methods 4.1 BBB permeation data 4.1.1 Bound and unbound drug concepts The drug is available in blood in the free (unbound) and bounded (protein bounded, erythrocyte bounded, tissue bounded) forms The unbound drug molecules equilibrate across the BBB and brain The spaces that these equilibria occur are: blood, interstitial fluid, intercellular and intracellular fluids... pericytes, astrocytes and microglia The BMVECs are surrounded by a basement membrane which composed of structural proteins (collagen and elastin), specialized proteins (fibronectin and laminin) and proteoglycans This structural specificity gives the basement membrane a cell establishment role Pericytes are cellular constituents of microvessels 4 Toxicity and Drug Testing including capillaries and post capillary... discovery studies (both peripheral and CNS drugs) and different methods developed in order to study the pharmacokinetic profile of drug candidates BBB permeability depends on physicochemical properties of drug compound and physiologic functions of the BBB (physical barrier, transport, metabolic pathways) and need special study techniques These techniques include in vivo, in vitro, and in silico methods (Diagram... world GLIA Vol 59, pp 177-187 Read, K D & Braggio, S (2010) Assessing brain free fraction in early drug discovery Expert Opinion on Drug Metabolism and Toxicology Vol 6, pp 337-344 24 Toxicity and Drug Testing Reichel, A (2009) Addressing Central Nervous System (CNS) Penetration in Drug Discovery: Basics and Implications of the Evolving New Concept Chemistry & Biodiversity Vol 6, pp 2030-2049 Rooy, I.; . TOXICITY AND DRUG TESTING Edited by William Acree Toxicity and Drug Testing Edited by William Acree Published by. excretion and toxicity) of potential drug candidates. Modern drug design also includes in silico computation methods to estimate ADMET properties, and several predictive methods are presented for drug. Anti cancer and anti HIV Drugs Efflux Breast cancer resistant proteins Drugs and xenobiotics (overlap with P-glycoproteins and multi- drug resistance proteins) Some anti cancer Drugs Efflux