Discovering drugs through biological transformation: role of pharmacologically active metabolites in drug discovery.

Bristol Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08534, Bristol-Myers Squibb, Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, Connecticut 06492, Bristol Myers Squibb, Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543, and Bristol-Myers Squibb, Pharmaceutical Research Institute, One Squibb Drive, New Brunswick, New Jersey 08903

[1]  F. McLafferty Interpretation of Mass Spectra , 1966 .

[2]  J. Rosazza,et al.  Microbial models of mammalian metabolism. Aromatic hydroxylation. , 1974, Archives of biochemistry and biophysics.

[3]  J. Rosazza,et al.  Microbial models of mammalian metabolism. , 1975, Journal of pharmaceutical sciences.

[4]  F. Sariaslani,et al.  Induction of cytochrome P-450 in Streptomyces griseus by soybean flour. , 1986, Biochemical and biophysical research communications.

[5]  A. Rossier Letter to the Editor , 1986, Paraplegia.

[6]  E. Radwanski,et al.  Pharmacokinetics and Dose Proportionality of Loratadine , 1987, Journal of clinical pharmacology.

[7]  E. Radwanski,et al.  Loratadine: Multiple‐Dose Pharmacokinetics , 1987, Journal of clinical pharmacology.

[8]  C. Fenselau,et al.  Species-dependent glucuronidation of drugs by immobilized rabbit, rhesus monkey, and human UDP-glucuronyltransferases. , 1987, Drug metabolism and disposition: the biological fate of chemicals.

[9]  S. Joel,et al.  ANALGESIC ACTIVITY OF MORPHINE-6-GLUCURONIDE , 1988, The Lancet.

[10]  F. Gonzalez,et al.  The molecular biology of cytochrome P450s. , 1988, Pharmacological reviews.

[11]  G. E. Martin, A. S. Zektzer: Two‐Dimensional NMR Methods for Establishing Molecular Connectivity. A Chemist's Guide to Experiment Selection, Performance, and Interpretation. VCH Verlagsgesellschaft, Weinheim, Basel, Cambridge, New York 1988. 245 Seiten, Preis: 126,00 DM. , 1989 .

[12]  H. Thaler,et al.  Chronic morphine therapy for cancer pain , 1991, Neurology.

[13]  F. Gonzalez,et al.  Expression of mammalian cytochrome P450 using baculovirus. , 1991, Methods in enzymology.

[14]  D. Jollow,et al.  The role of N-hydroxyphenetidine in phenacetin-induced hemolytic anemia. , 1991, Toxicology and applied pharmacology.

[15]  G. Mulder,et al.  Immobilization of solubilized UDP-glucuronosyltransferase from rat liver microsomes to Sepharose 4B. , 1992, Biochemical pharmacology.

[16]  H. Kim,et al.  Purification and characterization of novel sulfotransferase obtained from Klebsiella K-36, an intestinal bacterium of rat. , 1992, Journal of biochemistry.

[17]  A. Pfeifer,et al.  Simian virus 40 large tumor antigen-immortalized normal human liver epithelial cells express hepatocyte characteristics and metabolize chemical carcinogens. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[18]  D. Wortham,et al.  Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences. , 1993, JAMA.

[19]  F. Guengerich,et al.  Oxidation of the antihistaminic drug terfenadine in human liver microsomes. Role of cytochrome P-450 3A(4) in N-dealkylation and C-hydroxylation. , 1993, Drug metabolism and disposition: the biological fate of chemicals.

[20]  I. Wilson,et al.  High-performance liquid chromatography coupled to high-field proton nuclear magnetic resonance spectroscopy: application to the urinary metabolites of ibuprofen. , 1993, Analytical chemistry.

[21]  Y Chen,et al.  Mechanism of the cardiotoxic actions of terfenadine. , 1993, JAMA.

[22]  A. Bruins Atmospheric-pressure-ionization mass spectrometry: II. Applications in pharmacy, biochemistry and general chemistry☆ , 1994 .

[23]  I. Wilson,et al.  Evaluation of liquid chromatography coupled with high‐field 1H NMR spectroscopy for drug metabolite detection and characterization: The identification of paracetamol metabolites in urine and bile , 1994, NMR in biomedicine.

[24]  Paul A. Keifer,et al.  High-Resolution 1H NMR in Solid-Phase Organic Synthesis , 1994 .

[25]  K. Albert On-line use of NMR detection in separation chemistry , 1995 .

[26]  C. Cerniglia,et al.  Biotransformation of amitriptyline by Cunninghamella elegans. , 1995, Drug metabolism and disposition: the biological fate of chemicals.

[27]  Paul A. Keifer,et al.  WET Solvent Suppression and Its Applications to LC NMR and High-Resolution NMR Spectroscopy , 1995 .

[28]  Frank S. Pullen,et al.  ‘On‐line’ liquid chromatography/nuclear magnetic resonance mass spectrometry—a powerful spectroscopic tool for the analysis of mixtures of pharmaceutical interest , 1995 .

[29]  W. Crumb,et al.  Blockade of multiple human cardiac potassium currents by the antihistamine terfenadine: possible mechanism for terfenadine-associated cardiotoxicity. , 1995, Molecular pharmacology.

[30]  R. Baldessarini Drugs and the treatment of psychiatric disorders , 1996 .

[31]  S. Braun,et al.  100 and more basic NMR experiments , 1996 .

[32]  M. Snow,et al.  Identification of human liver cytochrome P450 enzymes that metabolize the nonsedating antihistamine loratadine. Formation of descarboethoxyloratadine by CYP3A4 and CYP2D6. , 1996, Biochemical pharmacology.

[33]  C. Cerniglia,et al.  Phase I and phase II enzymes produced by Cunninghamella elegans for the metabolism of xenobiotics. , 1996, FEMS microbiology letters.

[34]  I. Wilson,et al.  The development and application of coupled HPLC-NMR spectroscopy. , 1996, Advances in chromatography.

[35]  S. Ekins Past, present, and future applications of precision-cut liver slices for in vitro xenobiotic metabolism. , 1996, Drug metabolism reviews.

[36]  J P Shockcor,et al.  Combined HPLC, NMR spectroscopy, and ion-trap mass spectrometry with application to the detection and characterization of xenobiotic and endogenous metabolites in human urine. , 1996, Analytical chemistry.

[37]  H. Davis,et al.  In vivo metabolism-based discovery of a potent cholesterol absorption inhibitor, SCH58235, in the rat and rhesus monkey through the identification of the active metabolites of SCH48461. , 1997, The Journal of pharmacology and experimental therapeutics.

[38]  C. W. Fisher,et al.  Metabolism of the antiandrogenic drug (Flutamide) by human CYP1A2. , 1997, Drug metabolism and disposition: the biological fate of chemicals.

[39]  F. Gonzalez,et al.  Coexpression of cytochrome P4502A6 and human NADPH-P450 oxidoreductase in the baculovirus system. , 1997, Drug metabolism and disposition: the biological fate of chemicals.

[40]  Walter A. Korfmacher,et al.  HPLC-API/MS/MS : a powerful tool for integrating drug metabolism into the drug discovery process , 1997 .

[41]  L. Griffiths,et al.  Optimization of LC–NMR. III—Increased signal‐to‐noise ratio through column trapping , 1998 .

[42]  R. White,et al.  Short- and long-term projections about the use of drug metabolism in drug discovery and development. , 1998, Drug metabolism and disposition: the biological fate of chemicals.

[43]  J. Clader,et al.  Discovery of 1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4 -hydroxyphenyl)-2-azetidinone (SCH 58235): a designed, potent, orally active inhibitor of cholesterol absorption. , 1998, Journal of medicinal chemistry.

[44]  Y. Shu,et al.  1-Methoxy-agroclavine from Penicillium sp. WC75209, a novel inhibitor of the Lck tyrosine kinase. , 1998, Bioorganic & medicinal chemistry letters.

[45]  R. J. Anderson,et al.  Sulfation of minoxidil by multiple human cytosolic sulfotransferases. , 1998, Chemico-biological interactions.

[46]  A. P. Land,et al.  Application of liquid chromatography-mass spectrometry(n) analyses to the characterization of novel glyburide metabolites formed in vitro. , 1998, Journal of chromatography. A.

[47]  J. Henion,et al.  Atmospheric pressure ionization LC/MS/MS techniques for drug disposition studies. , 1998, Journal of pharmaceutical sciences.

[48]  1-Methoxy-agroclavine from Penicillium sp. WC75209, a Novel Inhibitor of the Lck Tyrosine Kinase. , 1998 .

[49]  A. Soldner,et al.  A radioreceptor assay for the analysis of AT1-receptor antagonists. Correlation with complementary LC data reveals a potential contribution of active metabolites. , 1998, Journal of pharmaceutical and biomedical analysis.

[50]  C L Crespi,et al.  The use of heterologously expressed drug metabolizing enzymes--state of the art and prospects for the future. , 1999, Pharmacology & therapeutics.

[51]  A. D. Rodrigues,et al.  Integrated cytochrome P450 reaction phenotyping: attempting to bridge the gap between cDNA-expressed cytochromes P450 and native human liver microsomes. , 1999, Biochemical pharmacology.

[52]  E. Abourashed,et al.  Microbial models of mammalian metabolism of xenobiotics: An updated review. , 1999, Current medicinal chemistry.

[53]  I. J. Fraser,et al.  The rapid identification of drug metabolites using capillary liquid chromatography coupled to an ion trap mass spectrometer. , 1999, Rapid communications in mass spectrometry : RCM.

[54]  U. Holzgrabe,et al.  NMR spectroscopy in drug development and analysis , 1999 .

[55]  Z. Ouyang,et al.  Comparison of plasma sample purification by manual liquid-liquid extraction, automated 96-well liquid-liquid extraction and automated 96-well solid-phase extraction for analysis by high-performance liquid chromatography with tandem mass spectrometry. , 1999, Journal of chromatography. B, Biomedical sciences and applications.

[56]  S. Sisenwine,et al.  Rapid drug metabolite profiling using fast liquid chromatography, automated multiple-stage mass spectrometry and receptor-binding. , 1999, Journal of chromatography. A.

[57]  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.

[58]  R. Azerad Microbial models for drug metabolism. , 1999, Advances in biochemical engineering/biotechnology.

[59]  Rodrigues Ad,et al.  Integrated Cytochrome P450 Reaction Phenotyping: Attempting to Bridge the Gap Between cDNA-expressed Cytochromes P450 and Native Human Liver Microsomes , 1999 .

[60]  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.

[61]  M. Mattila,et al.  Variations among non-sedating antihistamines: are there real differences? , 1999, European Journal of Clinical Pharmacology.

[62]  Gérard Hopfgartner,et al.  Exact mass measurement of product ions for the structural elucidation of drug metabolites with a tandem quadrupole orthogonal-acceleration time-of-flight mass spectrometer , 1999 .

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

[64]  T. Rushmore,et al.  Bioreactor systems in drug metabolism: synthesis of cytochrome P450-generated metabolites. , 2000, Metabolic engineering.

[65]  Biocatalytic Production of Pravastatin, an Anticholesterol Drug , 2000 .

[66]  J. Ritter Roles of glucuronidation and UDP-glucuronosyltransferases in xenobiotic bioactivation reactions. , 2000, Chemico-biological interactions.

[67]  Desloratadine: A preclinical and clinical overview. , 2001, Drugs of today.

[68]  M. Strolin Benedetti,et al.  Absorption, distribution, metabolism and excretion of [14C]levocetirizine, the R enantiomer of cetirizine, in healthy volunteers , 2001, European Journal of Clinical Pharmacology.

[69]  S. Wrighton,et al.  The role of hepatic and extrahepatic UDP-glucuronosyltransferases in human drug metabolism*† , 2001, Drug metabolism reviews.

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

[71]  J. Taskinen,et al.  Glucuronidation of 1-hydroxypyrene by human liver microsomes and human UDP-glucuronosyltransferases UGT1A6, UGT1A7, and UGT1A9: development of a high-sensitivity glucuronidation assay for human tissue. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[72]  J. Griffin,et al.  Cryogenic probe 13C NMR spectroscopy of urine for metabonomic studies. , 2002, Analytical chemistry.

[73]  Liang-Shang Gan,et al.  Delineating novel metabolic pathways of DPC 963, a non-nucleoside reverse transcriptase inhibitor, in rats. Characterization of glutathione conjugates of postulated oxirene and benzoquinone imine intermediates by LC/MS and LC/NMR. , 2002, Chemical research in toxicology.

[74]  Antony Williams,et al.  Applications of computer software for the interpretation and management of mass spectrometry data in pharmaceutical science. , 2002, Current topics in medicinal chemistry.

[75]  Use of a liquid chromatography/ion trap mass spectrometry/triple quadrupole mass spectrometry system for metabolite identification. , 2002, Rapid communications in mass spectrometry : RCM.

[76]  R. Ramanathan,et al.  Application of semi-automated metabolite identification software in the drug discovery process for rapid identification of metabolites and the cytochrome P450 enzymes responsible for their formation. , 2002, Journal of pharmaceutical and biomedical analysis.

[77]  Daniel Marek,et al.  High-resolution capillary tube NMR. A miniaturized 5-microL high-sensitivity TXI probe for mass-limited samples, off-line LC NMR, and HT NMR. , 2002, Analytical chemistry.

[78]  M. Hedeland,et al.  Identification of glucuronide conjugates of ketobemidone and its phase I metabolites in human urine utilizing accurate mass and tandem time-of-flight mass spectrometry. , 2002, Journal of mass spectrometry : JMS.

[79]  J. Magdalou,et al.  Comparison of electrospray, atmospheric pressure chemical ionization, and atmospheric pressure photoionization in the identification of apomorphine, dobutamine, and entacapone phase II metabolites in biological samples. , 2002, Analytical chemistry.

[80]  R. Mortishire-Smith,et al.  Metabolic profiling of rodent biological fluids via 1H NMR spectroscopy using a 1 mm microlitre probe. , 2002, The Analyst.

[81]  Hydroxylation of Mutilin by Streptomyces griseus and Cunninghamella echinulata , 2002 .

[82]  H. Kamimori,et al.  Synthesis of acylglucuronides of drugs using immobilized dog liver microsomes octadecylsilica particles coated with phospholipid. , 2003, Analytical biochemistry.

[83]  J. Bauman,et al.  Reaction phenotyping in drug discovery: moving forward with confidence? , 2003, Current drug metabolism.

[84]  B. Schmidt,et al.  Angiotensin II AT1 receptor antagonists. Clinical implications of active metabolites. , 2003, Journal of medicinal chemistry.

[85]  R. Kostiainen,et al.  Liquid chromatography/atmospheric pressure ionization-mass spectrometry in drug metabolism studies. , 2003, Journal of mass spectrometry : JMS.

[86]  S. Keam,et al.  Desloratadine , 2012, Drugs.

[87]  Zheng Ouyang,et al.  A strategy for metabolite identification using triple-quadrupole mass spectrometry with enhanced resolution and accurate mass capability. , 2003, Rapid communications in mass spectrometry : RCM.

[88]  S. Appajosyula,et al.  Efficacy and safety profile of fexofenadine HCl: a unique therapeutic option in H1-receptor antagonist treatment. , 2003, The Journal of allergy and clinical immunology.

[89]  Jacques Vervoort,et al.  LC-UV-solid-phase extraction-NMR-MS combined with a cryogenic flow probe and its application to the identification of compounds present in Greek oregano. , 2003, Analytical chemistry.

[90]  G. Hopfgartner,et al.  Rapid screening and characterization of drug metabolites using a new quadrupole-linear ion trap mass spectrometer. , 2003, Journal of mass spectrometry : JMS.

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

[92]  R. Mortishire-Smith,et al.  Metabolite identification in drug discovery. , 2003, Current opinion in drug discovery & development.

[93]  David Q. Liu,et al.  Use of a quadrupole linear ion trap mass spectrometer in metabolite identification and bioanalysis. , 2003, Rapid communications in mass spectrometry : RCM.

[94]  J. Clader The discovery of ezetimibe: a view from outside the receptor. , 2004, Journal of medicinal chemistry.

[95]  Z. Shahrokh,et al.  Mass Spectrometry Innovations in Drug Discovery and Development , 2001, Pharmaceutical Research.

[96]  G. Siest,et al.  Immobilization of microsomes into alginate beads is a convenient method for producing glucuronides from drugs , 1991, Applied Microbiology and Biotechnology.