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Denaturing high-performance liquid chromatography (DHPLC) is an accurate and efficient screening technique used for detecting deoxyribonucleic acid sequence changes by heteroduplex analysis. It can also be used for genotyping of single-nucleotide polymorphisms. The hi ...

The analysis of human genetic variations, such as single-nucleotide polymorphisms (SNPs), has great applications in genome-wide association studies of complex genetic traits. We have developed an SNP genotyping method based on the primer extension assay with fluorescence quenc ...

The Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB) is an interactive tool for researchers investigating how genetic variation effects drug response. The PharmGKB web site, http://www.pharmgkb.org, displays genotype, molecular, and clinical primary da ...

Recent breakthroughs in biological research have been made possible by remarkable advances in high-performance computing and the establishment of a highly sophisticated information technology infrastructure. This chapter gives an overview of the main and most important tec ...

Bifunctional DNA damaging agents continue to be the mainstay in various chemotherapeutic regimens used in the clinic. DNA interstrand crosslinks are considered to be the critical cytotoxic lesions for the biological activity of such agents. Gel-based electrophoretic assays can e ...

The Single Cell Gel Electrophoresis (Comet) assay, originally developed to allow visualisation of DNA strand break damage in individual cells, has been adapted to measure DNA interstrand cross-links. DNA interstrand cross-links are formed in cells by a number of commonly used cancer che ...

Anomalous scattering is commonly used to solve X-ray structures. As discussed here, anomalous scattering is also useful for characterizing complex systems with mixed and partial occupancies, where true electron density is represented by unresolvable ensemble averages. The sol ...

We describe a molecular modelling method for calculating the binding affinity of ligands for DNA. Though theoretically applicable to any form of noncovalent interaction, we concentrate on the case of predicting the sequence selectivity of a minor-groove binding ligand. The method is ba ...

The mouse lymphoma assay (MLA) using the thymidine kinase (Tk1) gene is widely used to detect the potential genotoxicity of a wide variety of chemical agents. The assay is recommended as a part of the core battery of genetic toxicology tests. Although the assay was developed more than 30 yr ago, there have ...

The use of the human S9 fraction in mutagenicity testing systems may be valuable for evaluating the mutagenicity of chemicals in humans. When using a crude human liver S9 fraction, which is obtained following the centrifugation of the tissue homogenate for 20 min at 9000g, in the Ames test, we may somet ...

The human homologue of the ether-a-go-go-related-gene (HERG) has been implicated in the “iatrogenic” long QT syndrome, with several products withdrawn from the market because of their interaction with this K + channel. The resultant impact on the pharmaceutical industry has been profou ...

From a pharmaceutical research point of view, it seems reasonable in the early phase of discovery to eliminate those drug candidates that are subject to bioactivation to electrophilic intermediates. Although rarely detectable per se, the structures of these intermediates often can be ...

Acyl glucuronides are unstable at physiologic pH and thus can result in free aglycone by hydrolysis and lead to positional isomers by acyl migration. Acylmigrated glucuronide isomers were shown to bind covalently to proteins in vitro and in vivo, causing potential toxicity, but the toxico ...

The Caco-2 cell culture model is used to determine the absorption potentials of drug candidates and the transport and metabolism mechanisms of drugs and dietary chemicals. The Food and Drug Administration (FDA) recognized the model system as useful in classifying a compound’s absorption ...

The parallel artificial membrane permeability assay (PAMPA), as a passive-permeability screen, is an excellent alternative to cellular models for the earliest absorption, distribution, metabolism, and excretion (ADME) primary screening of research compounds. PAMPA’s popu ...

The single-pass perfused rat intestinal model is an in situ perfusion method that can be used to determine regional disposition of drugs. It is useful for selecting a development candidate from a series of active compounds and for studying mechanisms of absorption and excretion. It is also usef ...

Drug permeability through cell monolayer is known to correlate well with in situ intestinal permeability and/or oral bioavailability. Several mammalian cell lines such as Caco-2, MDCK, MDCKII, and LLC-PK have been used to predict in vivo intestinal absorption of drugs. However, there are no ...

Drug transporters have been isolated from many tissues, including the intestines, liver, kidney, blood-brain barrier, and placenta, in animals and humans. There is increasing evidence that they play a very important role in drug absorption and disposition. By gaining a better understan ...

P-Glycoprotein (P-gp) is a multidrug transporter responsible for resistance to anticancer chemotherapy and physiologically involved in absorption, distribution, and excretion of a large number of hydrophobic xenobiotics. P-gp exhibits both an adenosine triphosphatase ( ...

This chapter focuses on the three most widely used in vitro protein binding techniques in pharmaceutical research, which each reflect a diversity of speed, data quality, and complexity. Chromatographic separation using a human serum albumin-immobilized column to allow relative ra ...