Evolving Role of Mass Spectrometry in Drug Discovery and Development

1.1 Route to Market: Discovery and Development of New Drugs 2 1.1.1 Industry Research and Development 2 1.1.2 Drug Discovery and Development Process 4 1.1.2.1 Drug Discovery 5 1.1.2.2 Drug Development 7 1.1.2.2.1 The Drug Substance 7 1.1.2.2.2 Clinical Trials 8 1.2 Drug Metabolism and Pharmacokinetics in Drug Discovery and Development 10 1.3 Mass Spectrometry Fundamentals 11 1.3.1 History 12 1.3.2 Fundamental Concepts and Terms 13 1.3.2.1 Mass Terminology 13 1.3.2.2 Mass Calibration and Resolution 14 1.3.3 Mass Spectrometer Components 15 1.3.3.1 Sample Inlet and Source 15

[1]  R. Cooks,et al.  Ambient mass spectrometry using desorption electrospray ionization (DESI): instrumentation, mechanisms and applications in forensics, chemistry, and biology. , 2005, Journal of mass spectrometry : JMS.

[2]  P. Narciso,et al.  Determination of anti-HIV drug concentration in human plasma by MALDI-TOF/TOF. , 2006, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[3]  J. Veuthey,et al.  Restricted access materials and large particle supports for on-line sample preparation: an attractive approach for biological fluids analysis. , 2004, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[4]  A. Watt,et al.  An evaluation of a four-channel multiplexed electrospray tandem mass spectrometry for higher throughput quantitative analysis. , 2002, Analytical chemistry.

[5]  H. Maurer.  Current role of liquid chromatography–mass spectrometry in clinical and forensic toxicology , 2007, Analytical and bioanalytical chemistry.

[6]  E. Chan,et al.  Pharmacokinetic study of intraperitoneally administered troglitazone in mice using ultra-performance liquid chromatography/tandem mass spectrometry. , 2007, Rapid communications in mass spectrometry : RCM.

[7]  M. Guilhaus,et al.  Ion dispersion near parallel wire grids in orthogonal acceleration time-of-flight mass spectrometry: predicting the effect of the approach angle on resolution. , 2002, Rapid communications in mass spectrometry : RCM.

[8]  G. V. Van Berkel,et al.  Improved imaging resolution in desorption electrospray ionization mass spectrometry. , 2008, Rapid communications in mass spectrometry : RCM.

[9]  X. Tong,et al.  Characterization of a technique for rapid pharmacokinetic studies of multiple co-eluting compounds by LC/MS/MS. , 1999, Journal of pharmaceutical and biomedical analysis.

[10]  M. Jemal,et al.  Increased throughput in quantitative bioanalysis using parallel-column liquid chromatography with mass spectrometric detection. , 2001, Rapid communications in mass spectrometry : RCM.

[11]  A. Grange,et al.  Automated determination of precursor ion, product ion, and neutral loss compositions and deconvolution of composite mass spectra using ion correlation based on exact masses and relative isotopic abundances. , 2008, Rapid communications in mass spectrometry : RCM.

[12]  B. Matuszewski.  Standard line slopes as a measure of a relative matrix effect in quantitative HPLC-MS bioanalysis. , 2006, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[13]  O. Pelkonen,et al.  In vitro screening of drug metabolism during drug development: can we trust the predictions? , 2005, Expert opinion on drug metabolism & toxicology.

[14]  J. Henion,et al.  Atmospheric pressure ion-sampling system for liquid chromatography/mass spectrometry analyses on a benchtop mass spectrometer , 1992 .

[15]  Michael E. Swartz,et al.  UPLC™: An Introduction and Review , 2005 .

[16]  Mike S. Lee.  Integrated Strategies for Drug Discovery Using Mass Spectrometry: Lee/Integrated Strategies for Drug Discovery Using Mass Spectrometry , 2005 .

[17]  Vinod P. Shah,et al.  The history of bioanalytical method validation and regulation: Evolution of a guidance document on bioanalytical methods validation , 2007, The AAPS Journal.

[18]  T. L. Lloyd,et al.  High-speed gradient parallel liquid chromatography/tandem mass spectrometry with fully automated sample preparation for bioanalysis: 30 seconds per sample from plasma. , 2002, Rapid communications in mass spectrometry : RCM.

[19]  L. Romanyshyn,et al.  Bioanalytical applications of 'fast chromatography' to high-throughput liquid chromatography/tandem mass spectrometric quantitation. , 2000, Rapid communications in mass spectrometry : RCM.

[20]  Roger Guevremont,et al.  High-field asymmetric waveform ion mobility spectrometry: a new tool for mass spectrometry. , 2004, Journal of chromatography. A.

[21]  A. Marshall,et al.  Fourier transform ion cyclotron resonance mass spectrometry: a primer. , 1998, Mass spectrometry reviews.

[22]  Jef Adriaensen,et al.  Novel generic UPLC/MS/MS method for high throughput analysis applied to permeability assessment in early Drug Discovery. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[23]  R. Bakhtiar,et al.  Tracking problems and possible solutions in the quantitative determination of small molecule drugs and metabolites in biological fluids using liquid chromatography-mass spectrometry. , 2007, Journal of pharmacological and toxicological methods.

[24]  O. Mcconnell,et al.  Advantages of atmospheric pressure photoionization mass spectrometry in support of drug discovery. , 2005, Rapid communications in mass spectrometry : RCM.

[25]  S. Unger,et al.  A 96-well single-pot protein precipitation, liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the determination of muraglitazar, a novel diabetes drug, in human plasma. , 2006, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[26]  Walter A. Korfmacher,et al.  Simultaneous determination of a drug candidate and its metabolite in rat plasma samples using ultrafast monolithic column high-performance liquid chromatography/tandem mass spectrometry. , 2002, Rapid communications in mass spectrometry : RCM.

[27]  R. Panchagnula,et al.  Biopharmaceutic and pharmacokinetic aspects of variable bioavailability of rifampicin. , 2004, International journal of pharmaceutics.

[28]  G. Duncan,et al.  Removal of metabolite interference during liquid chromatography/tandem mass spectrometry using high‐field asymmetric waveform ion mobility spectrometry , 2005 .

[29]  W. Naidong,et al.  A sensitive LC/MS/MS method using silica column and aqueous-organic mobile phase for the analysis of loratadine and descarboethoxy-loratadine in human plasma. , 2003, Journal of pharmaceutical and biomedical analysis.

[30]  L. Cohen,et al.  Small molecule analysis by MALDI mass spectrometry , 2002, Analytical and bioanalytical chemistry.

[31]  Angus Nedderman,et al.  Analytical strategies for identifying drug metabolites. , 2007, Mass spectrometry reviews.

[32]  J. T. Wu,et al.  High-speed liquid chromatography/tandem mass spectrometry using a monolithic column for high-throughput bioanalysis. , 2001, Rapid communications in mass spectrometry : RCM.

[33]  Gordon L Amidon,et al.  A Mechanistic Approach to Understanding the Factors Affecting Drug Absorption: A Review of Fundamentals , 2002, Journal of clinical pharmacology.

[34]  H. Yamada,et al.  Induction of two UDP-glucuronosyltransferase isoforms sensitive to phenobarbital that are involved in morphine glucuronidation: production of isoform-selective antipeptide antibodies toward UGT1.1r and UGT2B1. , 1997, Drug metabolism and disposition: the biological fate of chemicals.

[35]  R. Weaver,et al.  Identification and reduction of ion suppression effects on pharmacokinetic parameters by polyethylene glycol 400. , 2006, Rapid communications in mass spectrometry : RCM.

[36]  L. Yang,et al.  Evaluation of a four-channel multiplexed electrospray triple quadrupole mass spectrometer for the simultaneous validation of LC/MS/MS methods in four different preclinical matrixes. , 2001, Analytical chemistry.

[37]  J. Veuthey,et al.  Recent developments in liquid chromatography--impact on qualitative and quantitative performance. , 2007, Journal of chromatography. A.

[38]  M. Belov,et al.  A new technique for unbiased external ion accumulation in a quadrupole two-dimensional ion trap for electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry. , 2001, Rapid communications in mass spectrometry : RCM.

[39]  M. J. Avery.  Quantitative characterization of differential ion suppression on liquid chromatography/atmospheric pressure ionization mass spectrometric bioanalytical methods. , 2003, Rapid communications in mass spectrometry : RCM.

[40]  Richard R. Cline,et al.  Follow-on biologics: competition in the biopharmaceutical marketplace. , 2006, Journal of the American Pharmacists Association : JAPhA.

[41]  Serge Rudaz,et al.  Matrix effect in LC-ESI-MS and LC-APCI-MS with off-line and on-line extraction procedures. , 2004, Journal of chromatography. A.

[42]  L. Wienkers,et al.  Advances in predicting CYP-mediated drug interactions in the drug discovery setting , 2006, Expert opinion on drug discovery.

[43]  J. Wolff,et al.  Investigation of the advanced functionalities of a hybrid quadrupole orthogonal acceleration time-of-flight mass spectrometer. , 2007, Rapid communications in mass spectrometry : RCM.

[44]  Stephanie Kubina,et al.  High-Field Asymmetric Waveform Ion Mobility Spectrometry , 2009 .

[45]  J. Henion,et al.  Quantitative liquid chromatographic-tandem mass spectrometric determination of orlistat in plasma with a quadrupole ion trap. , 1998, Journal of chromatography. B, Biomedical sciences and applications.

[46]  L. Di,et al.  Ultra-performance liquid chromatography/tandem mass spectrometric quantification of structurally diverse drug mixtures using an ESI-APCI multimode ionization source. , 2007, Rapid communications in mass spectrometry : RCM.

[47]  T. Baillie,et al.  Rapid liquid chromatography with tandem mass spectrometry-based screening procedures for studies on the biotransformation of drug candidates. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[48]  R. Naviaux,et al.  Mitochondrial DNA Mutation Detection by Electrospray Mass Spectrometry , 2007, Clinical chemistry.

[49]  Guodong Chen,et al.  Applications of LC/MS in structure identifications of small molecules and proteins in drug discovery. , 2007, Journal of mass spectrometry : JMS.

[50]  R. King,et al.  Description and validation of a staggered parallel high performance liquid chromatography system for good laboratory practice level quantitative analysis by liquid chromatography/tandem mass spectrometry. , 2002, Rapid communications in mass spectrometry : RCM.

[51]  T. Bueters,et al.  Combined approach for high-throughput preparation and analysis of plasma samples from exposure studies. , 2007, Rapid communications in mass spectrometry : RCM.

[52]  L. Yang,et al.  Applications of new liquid chromatography-tandem mass spectrometry technologies for drug development support. , 2001, Journal of chromatography. A.

[53]  J. Yates,et al.  Direct analysis of protein complexes using mass spectrometry , 1999, Nature Biotechnology.

[54]  Yuichi Sugiyama,et al.  Microdose clinical trial: quantitative determination of fexofenadine in human plasma using liquid chromatography/electrospray ionization tandem mass spectrometry. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[55]  A. Marino,et al.  Development of a quantitative LC-MS/MS analytical method coupled with turbulent flow chromatography for digoxin for the in vitro P-gp inhibition assay. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[56]  R. Clement,et al.  Disposition of desloratadine in healthy volunteers , 2005, Xenobiotica; the fate of foreign compounds in biological systems.

[57]  M. Cole,et al.  AutoScan: an automated workstation for rapid determination of mass and tandem mass spectrometry conditions for quantitative bioanalytical mass spectrometry. , 2000, Rapid communications in mass spectrometry : RCM.

[58]  Wilson Z Shou,et al.  Liquid chromatography/tandem mass spectrometric bioanalysis using normal-phase columns with aqueous/organic mobile phases - a novel approach of eliminating evaporation and reconstitution steps in 96-well SPE. , 2002, Rapid communications in mass spectrometry : RCM.

[59]  R. Clement,et al.  Disposition of loratadine in healthy volunteers , 2007, Xenobiotica; the fate of foreign compounds in biological systems.

[60]  Mohammed Jemal,et al.  Liquid chromatography/tandem mass spectrometry methods for quantitation of mevalonic acid in human plasma and urine: method validation, demonstration of using a surrogate analyte, and demonstration of unacceptable matrix effect in spite of use of a stable isotope analog internal standard. , 2003, Rapid communications in mass spectrometry : RCM.

[61]  Walter A. Korfmacher,et al.  Cassette-accelerated rapid rat screen: a systematic procedure for the dosing and liquid chromatography/atmospheric pressure ionization tandem mass spectrometric analysis of new chemical entities as part of new drug discovery. , 2001, Rapid communications in mass spectrometry : RCM.

[62]  Y. Hashimoto,et al.  Orthogonal trap time-of-flight mass spectrometer using a collisional damping chamber. , 2005, Rapid communications in mass spectrometry : RCM.

[63]  C Thomas Caskey,et al.  The drug development crisis: efficiency and safety. , 2007, Annual review of medicine.

[64]  R. Micetich,et al.  High-throughput caco-2 cell permeability screening by cassette dosing and sample pooling approaches using direct injection/on-line guard cartridge extraction/tandem mass spectrometry. , 2000, Rapid communications in mass spectrometry : RCM.

[65]  Responding Rapidly to FDA Drug Withdrawals: Design and Application of a New Approach for a Consumer Health Website , 2006, Journal of medical Internet research.

[66]  Jun Zhang,et al.  Historical review of sample preparation for chromatographic bioanalysis: pros and cons , 2007 .

[67]  A. Makarov,et al.  The Orbitrap: a new mass spectrometer. , 2005, Journal of mass spectrometry : JMS.

[68]  R. Lobrutto,et al.  The use of acquity UPLC in pharmaceutical development , 2005 .

[69]  S. Horning,et al.  The use of a hybrid linear trap/FT-ICR mass spectrometer for on-line high resolution/high mass accuracy bottom-up sequencing. , 2005, Journal of biomolecular techniques : JBT.

[70]  N. Srinivas,et al.  Assessment of dose proportionality of muraglitazar after repeated oral dosing in rats via a sparse sampling methodology , 2007, Biopharmaceutics & drug disposition.

[71]  O. Sparkman.  Mass Spectrometry Desk Reference , 2006 .

[72]  J. Drews.  Drug discovery: a historical perspective. , 2000, Science.

[73]  F. Guengerich,et al.  Cytochrome P450s and other enzymes in drug metabolism and toxicity , 2006, The AAPS Journal.

[74]  Walter A. Korfmacher,et al.  Investigation of matrix effects in bioanalytical high-performance liquid chromatography/tandem mass spectrometric assays: application to drug discovery. , 2003, Rapid communications in mass spectrometry : RCM.

[75]  Walter A. Korfmacher,et al.  Fast mass spectrometry-based methodologies for pharmaceutical analyses. , 2006, Combinatorial chemistry & high throughput screening.

[76]  R. Caprioli,et al.  Profiling and imaging of tissues by imaging ion mobility-mass spectrometry. , 2007, Journal of mass spectrometry : JMS.

[77]  S. Wren,et al.  Peak capacity in gradient ultra performance liquid chromatography (UPLC). , 2005, Journal of pharmaceutical and biomedical analysis.

[78]  Karla K Kopec,et al.  Target identification and validation in drug discovery: the role of proteomics. , 2005, Biochemical pharmacology.

[79]  T. Gillespie,et al.  A review of nanoelectrospray ionization applications for drug metabolism and pharmacokinetics. , 2006, Current drug metabolism.

[80]  K. Nakanishi,et al.  Monolithic silica columns for high-efficiency chromatographic separations. , 2002, Journal of chromatography. A.

[81]  R. Morrison,et al.  Higher-throughput screening for Caco-2 permeability utilizing a multiple sprayer liquid chromatography/tandem mass spectrometry system. , 2003, Rapid communications in mass spectrometry : RCM.

[82]  Daniel L Sweeney,et al.  Small molecules as mathematical partitions. , 2003, Analytical chemistry.

[83]  Tony W. T. Bristow,et al.  Improved precision and accuracy for high-performance liquid chromatography/Fourier transform ion cyclotron resonance mass spectrometric exact mass measurement of small molecules from the simultaneous and controlled introduction of internal calibrants via a second electrospray nebuliser. , 2004, Rapid communications in mass spectrometry : RCM.

[84]  Guangji Wang,et al.  Simultaneous determination of loratadine and pseudoephedrine sulfate in human plasma by liquid chromatography-electrospray mass spectrometry for pharmacokinetic studies. , 2005, Journal of pharmaceutical and biomedical analysis.

[85]  S. Hrudey,et al.  Detection of microcystins using electrospray ionization high-field asymmetric waveform ion mobility mass spectrometry/mass spectrometry. , 2000, Rapid communications in mass spectrometry : RCM.

[86]  A. Bruins.  Liquid chromatography-mass spectrometry with ionspray and electrospray interfaces in pharmaceutical and biomedical research. , 1991, Journal of chromatography.

[87]  M. Jemal,et al.  Increased productivity in quantitative bioanalysis using a monolithic column coupled with high-flow direct-injection liquid chromatography/tandem mass spectrometry. , 2006, Rapid communications in mass spectrometry : RCM.

[88]  S. Han,et al.  Determination of Glimepiride in Human Plasma by Liquid Chromatography− Electrospray Ionization Tandem Mass Spectrometry , 2004 .

[89]  Soga,et al.  Performance of a monolithic silica column in a capillary under pressure-driven and electrodriven conditions , 2000, Analytical chemistry.

[90]  C. Hop,et al.  Parallel extraction columns and parallel analytical columns coupled with liquid chromatography/tandem mass spectrometry for on-line simultaneous quantification of a drug candidate and its six metabolites in dog plasma. , 2001, Rapid communications in mass spectrometry : RCM.

[91]  R. Mundkowski,et al.  Selective and rapid liquid chromatography-mass spectrometry method for the quantification of rofecoxib in pharmacokinetic studies with humans. , 2001, Journal of chromatography. B, Biomedical sciences and applications.

[92]  R. King,et al.  Collection of selected reaction monitoring and full scan data on a time scale suitable for target compound quantitative analysis by liquid chromatography/tandem mass spectrometry. , 2003, Rapid communications in mass spectrometry : RCM.

[93]  Jeffrey B. Gross,et al.  Timing of New Black Box Warnings and Withdrawals for Prescription Medications , 2003 .

[94]  E. Kantharaj,et al.  The use of liquid chromatography-atmospheric pressure chemical ionization mass spectrometry to explore the in vitro metabolism of cyanoalkyl piperidine derivatives. , 2005, Biomedical chromatography : BMC.

[95]  Iain Beattie,et al.  Ultra-performance liquid chromatography coupled to quadrupole-orthogonal time-of-flight mass spectrometry. , 2004, Rapid communications in mass spectrometry : RCM.

[96]  D. Barnett,et al.  Quantitation of morphine and codeine in human urine using high-filed asymmetric waveform ion mobility spectrometry (FAIMS) with mass spectrometric detection. , 2001, Journal of analytical toxicology.

[97]  R. Cooks,et al.  Desorption electrospray ionization mass spectrometry for the analysis of pharmaceuticals and metabolites. , 2006, Rapid communications in mass spectrometry : RCM.

[98]  Walter A. Korfmacher,et al.  Direct plasma analysis of drug compounds using monolithic column liquid chromatography and tandem mass spectrometry. , 2003, Analytical chemistry.

[99]  P. Kebarle.  A brief overview of the present status of the mechanisms involved in electrospray mass spectrometry. , 2000, Journal of mass spectrometry : JMS.

[100]  H. Bu,et al.  High-throughput cytochrome P450 (CYP) inhibition screening via a cassette probe-dosing strategy. VI. Simultaneous evaluation of inhibition potential of drugs on human hepatic isozymes CYP2A6, 3A4, 2C9, 2D6 and 2E1. , 2001, Rapid communications in mass spectrometry : RCM.

[101]  R. W. Hansen,et al.  The price of innovation: new estimates of drug development costs. , 2003, Journal of health economics.

[102]  Z. Ouyang,et al.  Enhanced resolution triple-quadrupole mass spectrometry for fast quantitative bioanalysis using liquid chromatography/tandem mass spectrometry: investigations of parameters that affect ruggedness. , 2003, Rapid communications in mass spectrometry : RCM.

[103]  Wilson Z Shou,et al.  Simultaneously quantifying parent drugs and screening for metabolites in plasma pharmacokinetic samples using selected reaction monitoring information-dependent acquisition on a QTrap instrument. , 2005, Rapid communications in mass spectrometry : RCM.

[104]  J. DiMasi.  New drug development in the United States from 1963 to 1999 , 2001, Clinical pharmacology and therapeutics.

[105]  D A Smith,et al.  Design of drugs involving the concepts and theories of drug metabolism and pharmacokinetics , 1996, Medicinal research reviews.

[106]  E. Plummer.  Inhibition of Poly ( ADP-ribose ) polymerase – PARP , 2009 .

[107]  Ari Rantanen,et al.  FiD: a software for ab initio structural identification of product ions from tandem mass spectrometric data. , 2008, Rapid communications in mass spectrometry : RCM.

[108]  E. Kantharaj,et al.  Simultaneous measurement of drug metabolic stability and identification of metabolites using ion-trap mass spectrometry. , 2003, Rapid communications in mass spectrometry : RCM.

[109]  P. J. Todd,et al.  Mass Spectrometry: A Textbook , 2007 .

[110]  S. Itai,et al.  Physicochemical properties and bioavailability of carbamazepine polymorphs and dihydrate. , 2000, International journal of pharmaceutics.

[111]  A. Dell,et al.  A Novel Geometry Mass Spectrometer, the Q-TOF, for Low-Femtomole/Attomole-Range Biopolymer Sequencing , 1997, Journal of protein chemistry.

[112]  W. Lambert,et al.  Evaluation of automated single mass spectrometry to tandem mass spectrometry function switching for comprehensive drug profiling analysis using a quadrupole time-of-flight mass spectrometer. , 2000, Rapid communications in mass spectrometry : RCM.

[113]  N. Srinivas.  Changing need for bioanalysis during drug development. , 2008, Biomedical chromatography : BMC.

[114]  Sean Yu,et al.  High-throughput, accurate mass liquid chromatography/tandem mass spectrometry on a quadrupole time-of-flight system as a 'first-line' approach for metabolite identification studies. , 2008, Rapid communications in mass spectrometry : RCM.

[115]  Nicola C Hughes,et al.  Accurate mass measurement at enhanced mass-resolution on a triple quadrupole mass-spectrometer for the identification of a reaction impurity and collisionally-induced fragment ions of cabergoline. , 2003, Rapid communications in mass spectrometry : RCM.

[116]  K. Alton,et al.  Application of mass spectrometry for metabolite identification. , 2006, Current drug metabolism.

[117]  W. Shou,et al.  Simultaneous development of six LC-MS-MS methods for the determination of multiple analytes in human plasma. , 2002, Journal of pharmaceutical and biomedical analysis.

[118]  M. Senko,et al.  External accumulation of ions for enhanced electrospray ionization fourier transform ion cyclotron resonance mass spectrometry , 1997 .

[119]  G. Guiochon,et al.  Effects of high pressure in liquid chromatography. , 2005, Journal of chromatography. A.

[120]  Belen'kiĭ Bg,et al.  High-performance membrane chromatography. , 1995 .

[121]  John Bennan,et al.  Evaluation of extractables from product-contact surfaces , 2002 .

[122]  Jennifer H Granger,et al.  Increasing throughput and information content for in vitro drug metabolism experiments using ultra-performance liquid chromatography coupled to a quadrupole time-of-flight mass spectrometer. , 2005, Rapid communications in mass spectrometry : RCM.

[123]  E. Kerns,et al.  High throughput physicochemical profiling for drug discovery. , 2001, Journal of pharmaceutical sciences.

[124]  B. Matuszewski,et al.  Determination of rofecoxib (MK-0966), a cyclooxygenase-2 inhibitor, in human plasma by high-performance liquid chromatography with tandem mass spectrometric detection. , 2000, Journal of chromatography. B, Biomedical sciences and applications.

[125]  L. Romanyshyn,et al.  Ultra-fast gradient vs. fast isocratic chromatography in bioanalytical quantification by liquid chromatography/tandem mass spectrometry. , 2001, Rapid communications in mass spectrometry : RCM.

[126]  T N Thompson,et al.  Optimization of metabolic stability as a goal of modern drug design , 2001, Medicinal research reviews.

[127]  M. Wilm,et al.  Analytical properties of the nanoelectrospray ion source. , 1996, Analytical chemistry.

[128]  H. Rosing,et al.  Stable isotopically labeled internal standards in quantitative bioanalysis using liquid chromatography/mass spectrometry: necessity or not? , 2005, Rapid communications in mass spectrometry : RCM.

[129]  R. Plumb,et al.  High-throughput quantification for a drug mixture in rat plasma-a comparison of Ultra Performance liquid chromatography/tandem mass spectrometry with high-performance liquid chromatography/tandem mass spectrometry. , 2006, Rapid communications in mass spectrometry : RCM.

[130]  C. Prakash,et al.  Chapter 6 Metabolite identification by lc-ms: applications in drug discovery and development , 2005 .

[131]  Hong Mei.  Matrix Effects: Causes and Solutions , 2004 .

[132]  Nagesh R Palepu,et al.  Assessment of oral bioavailability enhancing approaches for SB-247083 using flow-through cell dissolution testing as one of the screens. , 2003, International journal of pharmaceutics.

[133]  Jonathan P. Williams,et al.  The use of recently described ionisation techniques for the rapid analysis of some common drugs and samples of biological origin. , 2006, Rapid communications in mass spectrometry : RCM.

[134]  Z. Cai,et al.  Simultaneous quantitative cassette analysis of drugs and detection of their metabolites by high performance liquid chromatography/ion trap mass spectrometry. , 2000, Rapid communications in mass spectrometry : RCM.

[135]  E. Thurman.  Accurate-mass identification of chlorinated and brominated products of 4-nonylphenol, nonylphenol dimers, and other endocrine disrupters. , 2006, Journal of mass spectrometry : JMS.

[136]  E M Faed,et al.  Properties of acyl glucuronides: implications for studies of the pharmacokinetics and metabolism of acidic drugs. , 1984, Drug metabolism reviews.

[137]  R. Talaat,et al.  Rapid metabolite identification with sub parts-per-million mass accuracy from biological matrices by direct infusion nanoelectrospray ionization after clean-up on a ZipTip and LTQ/Orbitrap mass spectrometry. , 2008, Rapid communications in mass spectrometry : RCM.

[138]  T N Thompson,et al.  Early ADME in support of drug discovery: the role of metabolic stability studies. , 2000, Current drug metabolism.

[139]  W. W. Johnson.  Cytochrome P450 inactivation by pharmaceuticals and phytochemicals: therapeutic relevance. , 2008, Drug metabolism reviews.

[140]  Abigail Jacobs,et al.  Drug metabolites in safety testing. , 2003, Toxicology and applied pharmacology.

[141]  C. Robinson,et al.  A tandem mass spectrometer for improved transmission and analysis of large macromolecular assemblies. , 2002, Analytical chemistry.

[142]  Robert Masse,et al.  Validation of a sensitive and automated 96-well solid-phase extraction liquid chromatography-tandem mass spectrometry method for the determination of desloratadine and 3-hydroxydesloratadine in human plasma. , 2003, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[143]  G. Hopfgartner,et al.  The impact of accurate mass measurements using quadrupole/time-of-flight mass spectrometry on the characterisation and screening , 2000 .

[144]  Prakash Kulkarni,et al.  Impurities in generic pharmaceutical development. , 2007, Advanced drug delivery reviews.

[145]  J. Gross.  Mass Spectrometry: A Textbook , 2007 .

[146]  R. Thakur,et al.  Atmospheric pressure photoionization. II. Dual source ionization. , 2004, Journal of chromatography. A.

[147]  T. P. Hill.  Phase 0 Trials: Are They Ethically Challenged? , 2007, Clinical Cancer Research.

[148]  D. S. Hage,et al.  System suitability in bioanalytical LC/MS/MS. , 2007, Journal of pharmaceutical and biomedical analysis.

[149]  R. Subramanian,et al.  Detecting and characterizing reactive metabolites by liquid chromatography/tandem mass spectrometry. , 2006, Journal of mass spectrometry : JMS.

[150]  R. Cody,et al.  Versatile new ion source for the analysis of materials in open air under ambient conditions. , 2005, Analytical chemistry.

[151]  David J Newman,et al.  Natural products as sources of new drugs over the period 1981-2002. , 2003, Journal of natural products.

[152]  J. Henion,et al.  A four-column parallel chromatography system for isocratic or gradient LC/MS analyses. , 2001, Analytical chemistry.

[153]  D. J. Douglas,et al.  A combined linear ion trap time-of-flight system with improved performance and MS(n) capabilities. , 2001, Rapid communications in mass spectrometry : RCM.

[154]  Andrew A. Signore,et al.  Pharmaceutical Industry Profile , 2005 .

[155]  R. Plumb,et al.  The use of turbulent flow chromatography/mass spectrometry for the rapid, direct analysis of a novel pharmaceutical compound in plasma. , 1997, Rapid communications in mass spectrometry : RCM.

[156]  Vinod P. Shah,et al.  Quantitative Bioanalytical Methods Validation and Implementation: Best Practices for Chromatographic and Ligand Binding Assays , 2007 .

[157]  J. Henion,et al.  Comparison between liquid chromatography-time of-flight mass spectrometry and selected reaction monitoring liquid chromatography-mass spectrometry for quantitative determination of idoxifene in human plasma. , 2001, Journal of chromatography. B, Biomedical sciences and applications.

[158]  D. Kassel,et al.  Applications of high-throughput ADME in drug discovery. , 2004, Current opinion in chemical biology.

[159]  R. Bakhtiar.  Integrated strategies for drug discovery using mass spectrometry , 2006, Journal of the American Society for Mass Spectrometry.

[160]  K. Brune,et al.  Investigation of the pharmacokinetics of celecoxib by liquid chromatography-mass spectrometry. , 2002, Biomedical chromatography : BMC.

[161]  Y. Hsieh,et al.  Simultaneous determination of nicotinic acid and its metabolites using hydrophilic interaction chromatography with tandem mass spectrometry. , 2005, Rapid communications in mass spectrometry : RCM.

[162]  A. Dell,et al.  High sensitivity collisionally-activated decomposition tandem mass spectrometry on a novel quadrupole/orthogonal-acceleration time-of-flight mass spectrometer. , 1996, Rapid communications in mass spectrometry : RCM.

[163]  H. Gove,et al.  :Measuring Mass: From Positive Rays to Proteins , 2003 .

[164]  D. T. Rossi,et al.  Quantification and rapid metabolite identification in drug discovery using API time-of-flight LC/MS. , 2000, Analytical chemistry.

[165]  R. Frank.  Regulation of follow-on biologics. , 2007, The New England journal of medicine.

[166]  B. Matuszewski,et al.  Matrix effect in quantitative LC/MS/MS analyses of biological fluids: a method for determination of finasteride in human plasma at picogram per milliliter concentrations. , 1998, Analytical chemistry.

[167]  R Scott Obach,et al.  SEEING THROUGH THE MIST: ABUNDANCE VERSUS PERCENTAGE. COMMENTARY ON METABOLITES IN SAFETY TESTING , 2005, Drug Metabolism and Disposition.

[168]  G. Deng,et al.  Applications of mass spectrometry in early stages of target based drug discovery. , 2006, Journal of pharmaceutical and biomedical analysis.

[169]  T. Olah,et al.  The effects of sample preparation methods on the variability of the electrospray ionization response for model drug compounds. , 1999, Rapid communications in mass spectrometry : RCM.

[170]  C. McEwen,et al.  Analysis of solids, liquids, and biological tissues using solids probe introduction at atmospheric pressure on commercial LC/MS instruments. , 2005, Analytical chemistry.

[171]  W. Humphreys,et al.  Comparative Metabolism of Radiolabeled Muraglitazar in Animals and Humans by Quantitative and Qualitative Metabolite Profiling , 2007, Drug Metabolism and Disposition.

[172]  A new hybrid electrospray Fourier transform mass spectrometer: design and performance characteristics. , 2006, Rapid communications in mass spectrometry : RCM.

[173]  T. Baillie,et al.  Integration of knowledge-based metabolic predictions with liquid chromatography data-dependent tandem mass spectrometry for drug metabolism studies: application to studies on the biotransformation of indinavir. , 2004, Analytical chemistry.

[174]  T. Baillie,et al.  Drug metabolites in safety testing. , 2002, Toxicology and applied pharmacology.

[175]  Y. Alnouti,et al.  Increase of the LC-MS/MS sensitivity and detection limits using on-line sample preparation with large volume plasma injection. , 2005, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[176]  L. A. Fenu,et al.  The Prediction of Drug Metabolism, Tissue Distribution, and Bioavailability of 50 Structurally Diverse Compounds in Rat Using Mechanism-Based Absorption, Distribution, and Metabolism Prediction Tools , 2007, Drug Metabolism and Disposition.

[177]  H. Bu,et al.  High-throughput cytochrome P450 (CYP) inhibition screening via cassette probe-dosing strategy. I. Development of direct injection/on-line guard cartridge extraction/tandem mass spectrometry for the simultaneous detection of CYP probe substrates and their metabolites. , 2000, Rapid communications in mass spectrometry : RCM.

[178]  M. Churchwell,et al.  Improving LC-MS sensitivity through increases in chromatographic performance: comparisons of UPLC-ES/MS/MS to HPLC-ES/MS/MS. , 2005, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[179]  T. Covey,et al.  Automated nanospray using chip-based emitters for the quantitative analysis of pharmaceutical compounds , 2005, Journal of the American Society for Mass Spectrometry.

[180]  Scott Peterman,et al.  An integrated method for metabolite detection and identification using a linear ion trap/Orbitrap mass spectrometer and multiple data processing techniques: application to indinavir metabolite detection. , 2008, Journal of mass spectrometry : JMS.

[181]  R. Iannucci,et al.  Disposition of the selective cholesterol absorption inhibitor ezetimibe in healthy male subjects. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[182]  Jim X. Shen,et al.  Orthogonal extraction/chromatography and UPLC, two powerful new techniques for bioanalytical quantitation of desloratadine and 3-hydroxydesloratadine at 25 pg/mL. , 2006, Journal of pharmaceutical and biomedical analysis.

[183]  K. Alton,et al.  Chapter 10 Oxidative metabolites of drugs and xenobiotics: lc-ms methods to identify and characterize in biological matrices , 2005 .

[184]  Gérard Hopfgartner,et al.  Q Trap MS: A New Tool for Metabolite Identification , 2004 .

[185]  Kristin A. Sannes-Lowery,et al.  Applications of ESI-MS in drug discovery: interrogation of noncovalent complexes , 2006, Nature Reviews Drug Discovery.

[186]  M. Swartz.  Ultra performance liquid chromatography (UPLC) : An introduction , 2005 .

[187]  C. Enke,et al.  Ion-trapping technique for ion/molecule reaction studies in the center quadrupole of a triple quadrupole mass spectrometer , 1988 .

[188]  J. Henion,et al.  Bioanalytical high-throughput selected reaction monitoring-LC/MS determination of selected estrogen receptor modulators in human plasma: 2000 samples/day. , 2000, Analytical chemistry.

[189]  Vinod P. Shah,et al.  Bioanalytical Method Validation—A Revisit with a Decade of Progress , 2000, Pharmaceutical Research.

[190]  Philip Judson,et al.  Predicting Drug Metabolism – An Evaluation of the Expert System METEOR , 2005, Chemistry & biodiversity.

[191]  T. Baillie,et al.  Bridging cheminformatic metabolite prediction and tandem mass spectrometry. , 2005, Drug discovery today.

[192]  Thomayant Prueksaritanont,et al.  Complicating factors in safety testing of drug metabolites: kinetic differences between generated and preformed metabolites. , 2006, Toxicology and applied pharmacology.

[193]  R. Purves,et al.  Electrospray ionization high-field asymmetric waveform ion mobility spectrometry-mass spectrometry. , 1999, Analytical chemistry.

[194]  Klaus Resch,et al.  Direct and fast determination of antiretroviral drugs by automated online solid-phase extraction-liquid chromatography-tandem mass spectrometry in human plasma , 2006, Clinical chemistry and laboratory medicine.

[195]  R Scott Obach,et al.  Metabolites and safety: What are the concerns, and how should we address them? , 2006, Chemical research in toxicology.

[196]  G. Guiochon,et al.  Influence of pressure on the properties of chromatographic columns. II. The column hold-up volume. , 2005, Journal of chromatography. A.

[197]  Liling. Fang,et al.  High-throughput liquid chromatography ultraviolet/mass spectrometric analysis of combinatorial libraries using an eight-channel multiplexed electrospray time-of-flight mass spectrometer. , 2002, Rapid communications in mass spectrometry : RCM.

[198]  Ming Gu,et al.  Accurate mass filtering of ion chromatograms for metabolite identification using a unit mass resolution liquid chromatography/mass spectrometry system. , 2006, Rapid communications in mass spectrometry : RCM.

[199]  D. Lubman,et al.  An ion trap storage/time-of-flight mass spectrometer , 1992 .

[200]  Naidong Weng,et al.  Systematic troubleshooting for LC/MS/MS. Part 2: Large-scale LC/MS/MS and automation , 2002 .

[201]  R. C. Garner,et al.  The use of accelerator mass spectrometry to obtain early human ADME/PK data , 2005, Expert opinion on drug metabolism & toxicology.

[202]  P. Bharatam,et al.  Solid-state characterization of rifampicin samples and its biopharmaceutic relevance. , 2004, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[203]  A. Ghosal,et al.  Chapter 12 Cytochrome p450 (cyp) and udp-glucuronosyltransferase (ugt) enzymes: role in drug metabolism, polymorphism, and identification of their involvement in drug metabolism , 2005 .

[204]  Jay P. Charlebois,et al.  Construction of a hybrid quadrupole/fourier transform ion cyclotron resonance mass spectrometer for versatile MS/MS above 10 kDa , 2004, Journal of the American Society for Mass Spectrometry.

[205]  D. J. Douglas,et al.  An interface with a linear quadrupole ion guide for an electrospray-ion trap mass spectrometer system. , 2000, Analytical chemistry.

[206]  Randall Purves,et al.  High-Field Asymmetric Waveform Ion Mobility Spectrometry (FAIMS) , 2010 .

[207]  I. Chernushevich,et al.  An introduction to quadrupole-time-of-flight mass spectrometry. , 2001, Journal of mass spectrometry : JMS.

[208]  R Z Harris,et al.  Pharmacokinetics and its role in small molecule drug discovery research , 2001, Medicinal research reviews.

[209]  Olga Kavetskaia,et al.  Development and application of a new on-line SPE system combined with LC-MS/MS detection for high throughput direct analysis of pharmaceutical compounds in plasma. , 2005, Journal of chromatography. A.

[210]  Walter Korfmacher.  Bioanalytical Assays in a Drug Discovery Environment , 2004 .

[211]  E. Kantharaj,et al.  Simultaneous measurement of metabolic stability and metabolite identification of 7-methoxymethylthiazolo[3,2-a]pyrimidin-5-one derivatives in human liver microsomes using liquid chromatography/ion-trap mass spectrometry. , 2005, Rapid communications in mass spectrometry : RCM.

[212]  J. Jorgenson,et al.  Very high pressure gradient LC/MS/MS. , 2001, Analytical chemistry.

[213]  J. Roeraade,et al.  Electrospray ionization mass spectrometry as a tool for determination of drug binding sites to human serum albumin by noncovalent interaction. , 2005, Rapid communications in mass spectrometry : RCM.

[214]  Nicola C Hughes,et al.  High-sensitivity quantitation of cabergoline and pergolide using a triple-quadrupole mass spectrometer with enhanced mass-resolution capabilities. , 2003, Journal of mass spectrometry : JMS.

[215]  A. Makarov,et al.  Interfacing the orbitrap mass analyzer to an electrospray ion source. , 2003, Analytical chemistry.

[216]  H. Bu,et al.  High-throughput cytochrome P450 (CYP) inhibition screening via cassette probe-dosing strategy: III. Validation of a direct injection/on-line guard cartridge extraction-tandem mass spectrometry method for CYP2C19 inhibition evaluation. , 2001, Journal of pharmaceutical and biomedical analysis.

[217]  B. Warrack,et al.  Utility of the hybrid LTQ-FTMS for drug metabolism applications. , 2006, Current drug metabolism.

[218]  J. Steehler.  Introduction to Mass Spectrometry:: Instrumentation, Applications, and Strategies for Data Interpretation , 2009 .

[219]  Pierre Thibault,et al.  Improvement in peptide detection for proteomics analyses using NanoLC-MS and high-field asymmetry waveform ion mobility mass spectrometry. , 2005, Analytical chemistry.

[220]  A. Hopkins,et al.  The druggable genome , 2002, Nature Reviews Drug Discovery.

[221]  Walter A. Korfmacher,et al.  Ultra-performance liquid chromatography/tandem mass spectrometric determination of testosterone and its metabolites in in vitro samples. , 2006, Rapid communications in mass spectrometry : RCM.

[222]  Z. Mester,et al.  Comparison of flow injection analysis electrospray mass spectrometry and tandem mass spectrometry and electrospray high-field asymmetric waveform ion mobility mass spectrometry and tandem mass spectrometry for the determination of underivatized amino acids. , 2006, Rapid communications in mass spectrometry : RCM.

[223]  Oliver Fiehn,et al.  A comprehensive urinary metabolomic approach for identifying kidney cancerr. , 2007, Analytical biochemistry.

[224]  Walter A. Korfmacher,et al.  Increasing speed and throughput when using HPLC-MS/MS systems for drug metabolism and pharmacokinetic screening. , 2006, Current drug metabolism.

[225]  Min-Su Chang,et al.  Evaluation of 384-well formatted sample preparation technologies for regulated bioanalysis. , 2007, Rapid communications in mass spectrometry : RCM.

[226]  M. Senko,et al.  A two-dimensional quadrupole ion trap mass spectrometer , 2002, Journal of the American Society for Mass Spectrometry.

[227]  Oliver Fiehn,et al.  Metabolomic database annotations via query of elemental compositions: Mass accuracy is insufficient even at less than 1 ppm , 2006, BMC Bioinformatics.

[228]  F. Švec,et al.  High-Performance Membrane Chromatography. A Novel Method of Protein Separation , 1990 .

[229]  H. Bu,et al.  High-throughput cytochrome P450 (CYP) inhibition screening via cassette probe-dosing strategy. II. Validation of a direct injection/on-line guard cartridge extraction-tandem mass spectrometry method for CYP2D6 inhibition assessment. , 2001, Journal of chromatography. B, Biomedical sciences and applications.

[230]  W. Weinmann,et al.  Ion suppression effects in liquid chromatography-electrospray-ionisation transport-region collision induced dissociation mass spectrometry with different serum extraction methods for systematic toxicological analysis with mass spectra libraries. , 2002, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[231]  R. Purves,et al.  MASS SPECTROMETRIC CHARACTERIZATION OF A HIGH-FIELD ASYMMETRIC WAVEFORM ION MOBILITY SPECTROMETER , 1998 .

[232]  Hartmut Derendorf,et al.  Modeling of Pharmacokinetic/Pharmacodynamic (PK/PD) Relationships: Concepts and Perspectives , 1999, Pharmaceutical Research.

[233]  P. Dawson.  Quadrupole mass analyzers: performance, design and some recent applications , 1986 .

[234]  E. Vesell.  Relationship Between Drug Distribution and Therapeutic Effects in Man , 1974 .

[235]  R. Rourick,et al.  High throughput log D determination using liquid chromatography-mass spectrometry. , 2001, Combinatorial chemistry & high throughput screening.

[236]  A. Tall,et al.  The failure of torcetrapib: was it the molecule or the mechanism? , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[237]  Comparison of conventional and enhanced mass resolution triple-quadrupole mass spectrometers for discovery bioanalytical applications. , 2003, Rapid communications in mass spectrometry : RCM.

[238]  J. Wieling.  LC-MS-MS experiences with internal standards , 2002 .

[239]  Z. Mester,et al.  Quantitation of amphetamine, methamphetamine, and their methylenedioxy derivatives in urine by solid-phase microextraction coupled with electrospray ionization-high-field asymmetric waveform ion mobility spectrometry-mass spectrometry. , 2002, Analytical chemistry.

[240]  R Graham Cooks,et al.  Direct characterization of enzyme-substrate complexes by using electrosonic spray ionization mass spectrometry. , 2005, Angewandte Chemie.

[241]  R. Mortishire-Smith,et al.  High-throughput bioanalysis with simultaneous acquisition of metabolic route data using ultra performance liquid chromatography coupled with time-of-flight mass spectrometry , 2006, Analytical and bioanalytical chemistry.

[242]  C. Young,et al.  Parallel high-throughput accurate mass measurement using a nine-channel multiplexed electrospray liquid chromatography ultraviolet time-of-flight mass spectrometry system. , 2003, Rapid communications in mass spectrometry : RCM.

[243]  Thilo A Fligge,et al.  Integration of a rapid automated solubility classification into early validation of hits obtained by high throughput screening. , 2006, Journal of pharmaceutical and biomedical analysis.

[244]  Yuan-Qing Xia,et al.  LC-MS Development strategies for quantitative bioanalysis. , 2006, Current drug metabolism.

[245]  M. Amad,et al.  Investigation of an enhanced resolution triple quadrupole mass spectrometer for high-throughput liquid chromatography/tandem mass spectrometry assays. , 2002, Rapid communications in mass spectrometry : RCM.

[246]  R. March.  An Introduction to Quadrupole Ion Trap Mass Spectrometry , 1997 .

[247]  James W. Hager,et al.  A new linear ion trap mass spectrometer , 2002 .

[248]  Han van de Waterbeemd,et al.  Property-Based Design: Optimization of Drug Absorption and Pharmacokinetics , 2001 .

[249]  Leimin Fan,et al.  Recent advances in high-throughput quantitative bioanalysis by LC-MS/MS. , 2007, Journal of pharmaceutical and biomedical analysis.

[250]  S. Walker,et al.  Pharmaceutical innovation by the seven UK-owned pharmaceutical companies (1964-1985). , 1988, British journal of clinical pharmacology.

[251]  J. Watson,et al.  Introduction to Mass Spectrometry: Instrumentation, Applications, and Strategies for Data Interpretation , 2007 .

[252]  K. Unger,et al.  Particle packed columns and monolithic columns in high-performance liquid chromatography-comparison and critical appraisal. , 2008, Journal of chromatography. A.

[253]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[254]  Z. Cai,et al.  High-throughput analysis in drug discovery: application of liquid chromatography/ion-trap mass spectrometry for simultaneous cassette analysis of alpha-1a antagonists and their metabolites in mouse plasma. , 2001, Rapid communications in mass spectrometry : RCM.

[255]  B. Matuszewski,et al.  Strategies for the assessment of matrix effect in quantitative bioanalytical methods based on HPLC-MS/MS. , 2003, Analytical chemistry.

[256]  D. Muntean,et al.  Determination of loratadine and its active metabolite in human plasma by high-performance liquid chromatography with mass spectrometry detection. , 2007, Journal of pharmaceutical and biomedical analysis.

[257]  Imma Ferrer,et al.  Importance of the electron mass in the calculations of exact mass by time-of-flight mass spectrometry. , 2007, Rapid communications in mass spectrometry : RCM.

[258]  R Scott Obach,et al.  Can in vitro metabolism-dependent covalent binding data in liver microsomes distinguish hepatotoxic from nonhepatotoxic drugs? An analysis of 18 drugs with consideration of intrinsic clearance and daily dose. , 2008, Chemical research in toxicology.

[259]  S. A. White,et al.  Evaluation of ultra-performance liquid chromatography in the bioanalysis of small molecule drug candidates in plasma. , 2007, Journal of chromatographic science.

[260]  L. Novotný,et al.  Liquid chromatographic-mass spectrometric determination of celecoxib in plasma using single-ion monitoring and its use in clinical pharmacokinetics. , 2001, Journal of chromatography. B, Biomedical sciences and applications.

[261]  J. Bauer,et al.  Ritonavir: An Extraordinary Example of Conformational Polymorphism , 2001, Pharmaceutical Research.

[262]  Quadrupole mass analyzers: theoretical and practical considerations , 2005 .

[263]  I. Kola,et al.  Can the pharmaceutical industry reduce attrition rates? , 2004, Nature Reviews Drug Discovery.

[264]  F. Zuiderweg,et al.  Longitudinal diffusion and resistance to mass transfer as causes of nonideality in chromatography , 1995 .

[265]  D. Newman,et al.  Natural products as sources of new drugs over the last 25 years. , 2007, Journal of natural products.

[266]  W. Tong,et al.  Impact of solid state properties on developability assessment of drug candidates. , 2004, Advanced drug delivery reviews.

[267]  Arun K Mandagere,et al.  Graphical model for estimating oral bioavailability of drugs in humans and other species from their Caco-2 permeability and in vitro liver enzyme metabolic stability rates. , 2002, Journal of medicinal chemistry.

[268]  Z. Mester,et al.  Separation and quantitation of the stereoisomers of ephedra alkaloids in natural health products using flow injection-electrospray ionization-high field asymmetric waveform ion mobility spectrometry-mass spectrometry. , 2003, Analytical chemistry.

[269]  J. T. Wu,et al.  Multiple-sprayer tandem mass spectrometry with parallel high flow extraction and parallel separation for high-throughput quantitation in biological fluids. , 2001, Rapid communications in mass spectrometry : RCM.

[270]  Ragu Ramanathan,et al.  Response normalized liquid chromatography nanospray ionization mass spectrometry , 2007, Journal of the American Society for Mass Spectrometry.

[271]  E. Furfine,et al.  Preclinical Pharmacology and Pharmacokinetics of GW433908, a Water-Soluble Prodrug of the Human Immunodeficiency Virus Protease Inhibitor Amprenavir , 2004, Antimicrobial Agents and Chemotherapy.

[272]  J. Syage,et al.  Atmospheric pressure photoionization. 1. General properties for LC/MS. , 2004, Analytical chemistry.

[273]  T. Baker,et al.  On-Line Solid Phase Extraction Using the Prospekt-2 Coupled with a Liquid Chromatography/Tandem Mass Spectrometer for the Determination of Dextromethorphan, Dextrorphan and Guaifenesin in Human Plasma , 2005, European journal of mass spectrometry.

[274]  M. Faul,et al.  Salt form selection and characterization of LY333531 mesylate monohydrate. , 2000, International journal of pharmaceutics.

[275]  A. Brockman,et al.  Evaluation of high-field asymmetric waveform ion mobility spectrometry coupled to nanoelectrospray ionization for bioanalysis in drug discovery. , 2007, Rapid communications in mass spectrometry : RCM.

[276]  W. Johnson.  Many drugs and phytochemicals can be activated to biological reactive intermediates. , 2008, Current drug metabolism.

[277]  W. Feng.  Mass spectrometry in drug discovery: a current review. , 2004, Current drug discovery technologies.

[278]  Timothy Olah,et al.  Mechanistic investigation of ionization suppression in electrospray ionization , 2000, Journal of the American Society for Mass Spectrometry.

[279]  Desmond O'Connor,et al.  Ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry for robust, high-throughput quantitative analysis of an automated metabolic stability assay, with simultaneous determination of metabolic data. , 2006, Rapid communications in mass spectrometry : RCM.

[280]  C. Bigogno,et al.  New perspectives in bio-analytical techniques for preclinical characterization of a drug candidate: UPLC-MS/MS in in vitro metabolism and pharmacokinetic studies. , 2007, Journal of pharmaceutical and biomedical analysis.