A guide to drug discovery: Making Better Drugs: Decision Gates in Non-Clinical Drug Development

Drug development is a risky business. Success or failure often depends on selecting one or two molecules for development from many choices offered by the engines of high-throughput discovery. A lead candidate needs to possess adequate bioactivity, appropriate physical–chemical properties to enable formulation development, the ability to cross crucial membranes, reasonable metabolic stability and appropriate safety and efficacy in humans. Predicting how a drug will behave in humans before clinical testing requires a battery of sophisticated in vitro tests that complement traditional in vivo animal safety assessments. This review discusses how to strategically identify which non-clinical studies should be performed to provide the required guidance and comfort to stakeholders involved in clinical drug testing.

[1]  Ann Thayer,et al.  GENOMICS MOVES ON , 2002 .

[2]  J. Lehmann,et al.  The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. , 1998, The Journal of clinical investigation.

[3]  D. Balkovetz.  Hepatocyte growth factor and Madin‐Darby canine kidney cells: In vitro models of epithelial cell movement and morphogenesis , 1998, Microscopy research and technique.

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

[5]  L. Moore,et al.  St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[6]  M. Hashimoto,et al.  [Draft ICH guideline S7B: guideline on safety pharmacology studies for assessing the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals]. , 2003, Nihon yakurigaku zasshi. Folia pharmacologica Japonica.

[7]  P. Artursson,et al.  Epithelial transport of drugs in cell culture. I: A model for studying the passive diffusion of drugs over intestinal absorptive (Caco-2) cells. , 1990, Journal of pharmaceutical sciences.

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

[9]  Charles W Schmidt.  Toxicogenomics. An emerging discipline. , 2003, EHP toxicogenomics : journal of the National Institute of Environmental Health Sciences.

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

[11]  L. Benet,et al.  Changes in plasma protein binding have little clinical relevance , 2002, Clinical pharmacology and therapeutics.

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

[13]  Shiew-Mei Huang,et al.  Assessment of the Quality and Quantity of Drug‐Drug Interaction Studies in Recent NDA Submissions: Study Design and Data Analysis Issues , 1999, Journal of clinical pharmacology.

[14]  James F. Young,et al.  MicroPET: a high resolution PET scanner for imaging small animals , 1996, IEEE Nuclear Science Symposium Conference Record.

[15]  P. Ader,et al.  P-glycoprotein transporters and the gastrointestinal tract: evaluation of the potential in vivo relevance of in vitro data employing talinolol as model compound. , 1998, International journal of clinical pharmacology and therapeutics.

[16]  C. January,et al.  HERG Channel Dysfunction in Human Long QT Syndrome , 1998, The Journal of Biological Chemistry.

[17]  A. Li,et al.  Cryopreserved human hepatocytes: characterization of drug-metabolizing enzyme activities and applications in higher throughput screening assays for hepatotoxicity, metabolic stability, and drug-drug interaction potential. , 1999, Chemico-biological interactions.

[18]  Stephen H. Friend,et al.  Toxicogenomics and drug discovery: will new technologies help us produce better drugs? , 2002, Nature Reviews Drug Discovery.

[19]  E. Groene.  Expression of cytochromes P450 in mammalian cells. , 1998 .

[20]  E Holmes,et al.  Nuclear magnetic resonance spectroscopic and principal components analysis investigations into biochemical effects of three model hepatotoxins. , 1998, Chemical research in toxicology.

[21]  T. Kronbach,et al.  Characterization of a common genetic defect of cytochrome P-450 function (debrisoquine-sparteine type polymorphism)--increased Michaelis is Constant (Km) and loss of stereoselectivity of bufuralol 1'-hydroxylation in poor metabolizers. , 1984, Biochemical and biophysical research communications.

[22]  R. E. White,et al.  High-throughput screening in drug metabolism and pharmacokinetic support of drug discovery. , 2000, Annual review of pharmacology and toxicology.

[23]  K Gubernator,et al.  Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes. , 1998, Journal of medicinal chemistry.

[24]  Walter A. Korfmacher,et al.  Systematic LC/MS metabolite identification in drug discovery. , 2001, Analytical chemistry.

[25]  K. Albert,et al.  Liquid chromatography-nuclear magnetic resonance spectroscopy. , 1999, Journal of chromatography. A.

[26]  Simon A Roberts.  Drug metabolism and pharmacokinetics in drug discovery. , 2003, Current opinion in drug discovery & development.

[27]  Shiew-Mei Huang,et al.  Optimizing Drug Development: Strategies to Assess Drug Metabolism/Transporter Interaction Potential—Toward a Consensus , 2001, Pharmaceutical Research.

[28]  M. Cayen.  Considerations in the Design of Toxicokinetic Programs , 1995, Toxicologic pathology (Print).

[29]  T. McDonald,et al.  HERG K+ Channel Activity Is Regulated by Changes in Phosphatidyl Inositol 4,5-Bisphosphate , 2001, Circulation research.

[30]  A. Y. Lu,et al.  Role of pharmacokinetics and metabolism in drug discovery and development. , 1997, Pharmacological reviews.

[31]  J. Tolan,et al.  MDCK (Madin-Darby canine kidney) cells: A tool for membrane permeability screening. , 1999, Journal of pharmaceutical sciences.

[32]  F. Gonzalez.  Overview of experimental approaches for study of drug metabolism and drug-drug interactions. , 1997, Advances in pharmacology.

[33]  H. Saito,et al.  Transepithelial transport of oral cephalosporins by monolayers of intestinal epithelial cell line Caco-2: specific transport systems in apical and basolateral membranes. , 1992, The Journal of pharmacology and experimental therapeutics.

[34]  Ann Daly,et al.  Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression , 2001, Nature Genetics.

[35]  K. Wasan,et al.  Influence of phytostanol phosphoryl ascorbate, FM-VP4, on pancreatic lipase activity and cholesterol accumulation within Caco-2 cells. , 2002, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[36]  B. Goodwin,et al.  The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. , 1999, Molecular pharmacology.

[37]  M K Bayliss,et al.  High-throughput pharmacokinetics: cassette dosing. , 1999, Current opinion in drug discovery & development.

[38]  M. Machida,et al.  High Throughput Prediction of Oral Absorption: Improvement of the Composition of the Lipid Solution Used in Parallel Artificial Membrane Permeation Assay , 2001, Journal of biomolecular screening.

[39]  M. Tarbit,et al.  A reporter gene assay to assess the molecular mechanisms of xenobiotic-dependent induction of the human CYP3A4 gene in vitro. , 1999, Xenobiotica; the fate of foreign compounds in biological systems.

[40]  G. Hawksworth,et al.  Advantages and Disadvantages of Using Human Cells for Pharmacological and Toxicological Studies , 1994, Human & experimental toxicology.

[41]  I. Wilson,et al.  19F-NMR and directly coupled HPLC-NMR-MS investigations into the metabolism of 2-bromo-4-trifluoromethylaniline in rat: a urinary excretion balance study without the use of radiolabelling. , 1998, Xenobiotica; the fate of foreign compounds in biological systems.

[42]  Kenneth S. Ramos,et al.  CYTOCHROME P-450 3 A 4 : Regulation and Role in Drug Metabolism , 2005 .

[43]  Sean Kim,et al.  CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[44]  A. Li,et al.  Primary hepatocyte cultures as an in vitro experimental model for the evaluation of pharmacokinetic drug-drug interactions. , 1997, Advances in pharmacology.

[45]  M. Eichelbaum.  Polymorphic drug oxidation in humans. , 1984, Federation proceedings.

[46]  A. Marshall,et al.  Scaling MS plateaus with high-resolution FT-ICRMS. , 2002, Analytical chemistry.

[47]  S. Roberts,et al.  High-throughput screening approaches for investigating drug metabolism and pharmacokinetics , 2001, Xenobiotica; the fate of foreign compounds in biological systems.

[48]  G. L. Kedderis,et al.  Present status of the application of cryopreserved hepatocytes in the evaluation of xenobiotics: consensus of an international expert panel. , 1999, Chemico-biological interactions.

[49]  C. Gunaratna.  Drug Metabolism & Pharmacokinetics in Drug Discovery : A Primer for Bioanalytical Chemists , Part I , 2000 .

[50]  Roberts Sa,et al.  High-throughput screening approaches for investigating drug metabolism and pharmacokinetics. , 2001 .

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

[52]  W Vaalburg,et al.  Positron emission tomography in drug development and drug evaluation. , 2000, Current pharmaceutical design.

[53]  E. M. de Groene,et al.  Development of human cytochrome P450-expressing cell lines: application in mutagenicity testing of ochratoxin A. , 1996, Cancer research.

[54]  A. Beresford,et al.  ADME/PK as part of a rational approach to drug discovery. , 2000, Drug discovery today.

[55]  Y. Rudy,et al.  Linking a genetic defect to its cellular phenotype in a cardiac arrhythmia , 1999, Nature.

[56]  F. Guengerich,et al.  Cytochrome P-450 3A4: regulation and role in drug metabolism. , 1999, Annual review of pharmacology and toxicology.

[57]  Per Artursson,et al.  Intestinal Drug Absorption and Metabolism in Cell Cultures: Caco-2 and Beyond , 1997, Pharmaceutical Research.