R S Obach

Summary

Affiliation: Pfizer Global Research and Development
Country: USA

Publications

  1. ncbi request reprint Measurement of Michaelis constants for cytochrome P450-mediated biotransformation reactions using a substrate depletion approach
    R Scott Obach
    Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton, Connecticut, USA
    Drug Metab Dispos 30:831-7. 2002
  2. ncbi request reprint Potent inhibition of human liver aldehyde oxidase by raloxifene
    R Scott Obach
    Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA
    Drug Metab Dispos 32:89-97. 2004
  3. ncbi request reprint Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study
    R Scott Obach
    Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Groton Laboratories, Pfizer, Inc, Groton, CT 06340, USA
    Drug Metab Dispos 33:262-70. 2005
  4. ncbi request reprint Mechanism of cytochrome P4503A4- and 2D6-catalyzed dehydrogenation of ezlopitant as probed with isotope effects using five deuterated analogs
    R S Obach
    Department of Drug Metabolism, Pfizer Global Research and Development, Groton, Connecticut 06340, USA
    Drug Metab Dispos 29:1599-607. 2001
  5. ncbi request reprint Metabolism of ezlopitant, a nonpeptidic substance P receptor antagonist, in liver microsomes: enzyme kinetics, cytochrome P450 isoform identity, and in vitro-in vivo correlation
    R S Obach
    Drug Metabolism Department, Pfizer Central Research, Groton, CT 06340, USA
    Drug Metab Dispos 28:1069-76. 2000
  6. doi request reprint Understanding the clinical pharmacokinetics of a GABAA partial agonist by application of in vitro tools
    Aarti D Sawant
    Department of Pharmacokinetics, Pharmacodynamics and Metabolism, Pfizer Global Research and Development, Groton New London Laboratories, Pfizer Inc, Groton, CT 06340, USA
    Xenobiotica 40:476-84. 2010
  7. ncbi request reprint Validated assays for human cytochrome P450 activities
    Robert L Walsky
    Pharacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer, Inc, Groton, Connecticut 06340, USA
    Drug Metab Dispos 32:647-60. 2004
  8. ncbi request reprint Human liver aldehyde oxidase: inhibition by 239 drugs
    R Scott Obach
    Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA
    J Clin Pharmacol 44:7-19. 2004
  9. ncbi request reprint Cytochrome P450-catalyzed metabolism of ezlopitant alkene (CJ-12,458), a pharmacologically active metabolite of ezlopitant: enzyme kinetics and mechanism of an alkene hydration reaction
    R S Obach
    Drug Metabolism, Pfizer, Inc, Groton, Connecticut
    Drug Metab Dispos 29:1057-67. 2001
  10. ncbi request reprint Nonspecific binding to microsomes: impact on scale-up of in vitro intrinsic clearance to hepatic clearance as assessed through examination of warfarin, imipramine, and propranolol
    R S Obach
    Department of Drug Metabolism, Pfizer Central Research, Groton, CT 06340, USA
    Drug Metab Dispos 25:1359-69. 1997

Detail Information

Publications88

  1. ncbi request reprint Measurement of Michaelis constants for cytochrome P450-mediated biotransformation reactions using a substrate depletion approach
    R Scott Obach
    Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton, Connecticut, USA
    Drug Metab Dispos 30:831-7. 2002
    ....
  2. ncbi request reprint Potent inhibition of human liver aldehyde oxidase by raloxifene
    R Scott Obach
    Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA
    Drug Metab Dispos 32:89-97. 2004
    ....
  3. ncbi request reprint Sertraline is metabolized by multiple cytochrome P450 enzymes, monoamine oxidases, and glucuronyl transferases in human: an in vitro study
    R Scott Obach
    Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Groton Laboratories, Pfizer, Inc, Groton, CT 06340, USA
    Drug Metab Dispos 33:262-70. 2005
    ..g., CYP2D6, CYP2C19, CYP2C9, UGT1A1) that could profoundly impact the pharmacokinetics of sertraline...
  4. ncbi request reprint Mechanism of cytochrome P4503A4- and 2D6-catalyzed dehydrogenation of ezlopitant as probed with isotope effects using five deuterated analogs
    R S Obach
    Department of Drug Metabolism, Pfizer Global Research and Development, Groton, Connecticut 06340, USA
    Drug Metab Dispos 29:1599-607. 2001
    ..8 to 5.9. Thus, dehydrogenation does not appear to occur via enzyme-mediated general acid catalysis of the benzyl alcohol. A mechanism for the dehydrogenation of ezlopitant is proposed in consideration of the data presented...
  5. ncbi request reprint Metabolism of ezlopitant, a nonpeptidic substance P receptor antagonist, in liver microsomes: enzyme kinetics, cytochrome P450 isoform identity, and in vitro-in vivo correlation
    R S Obach
    Drug Metabolism Department, Pfizer Central Research, Groton, CT 06340, USA
    Drug Metab Dispos 28:1069-76. 2000
    ..The apparent predominance of CYP3A over CYP2D6 is consistent with observations of the pharmacokinetics of ezlopitant in humans in vivo...
  6. doi request reprint Understanding the clinical pharmacokinetics of a GABAA partial agonist by application of in vitro tools
    Aarti D Sawant
    Department of Pharmacokinetics, Pharmacodynamics and Metabolism, Pfizer Global Research and Development, Groton New London Laboratories, Pfizer Inc, Groton, CT 06340, USA
    Xenobiotica 40:476-84. 2010
    ....
  7. ncbi request reprint Validated assays for human cytochrome P450 activities
    Robert L Walsky
    Pharacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer, Inc, Groton, Connecticut 06340, USA
    Drug Metab Dispos 32:647-60. 2004
    ..These methods should prove useful in the routine assessments of the potential for new drug candidates to elicit pharmacokinetic drug interactions via inhibition of cytochrome P450 activities...
  8. ncbi request reprint Human liver aldehyde oxidase: inhibition by 239 drugs
    R Scott Obach
    Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA
    J Clin Pharmacol 44:7-19. 2004
    ....
  9. ncbi request reprint Cytochrome P450-catalyzed metabolism of ezlopitant alkene (CJ-12,458), a pharmacologically active metabolite of ezlopitant: enzyme kinetics and mechanism of an alkene hydration reaction
    R S Obach
    Drug Metabolism, Pfizer, Inc, Groton, Connecticut
    Drug Metab Dispos 29:1057-67. 2001
    ..From these data, a mechanism for this reaction is proposed involving epoxidation, an exocyclic hydride shift, and reduction at the benzylic position...
  10. ncbi request reprint Nonspecific binding to microsomes: impact on scale-up of in vitro intrinsic clearance to hepatic clearance as assessed through examination of warfarin, imipramine, and propranolol
    R S Obach
    Department of Drug Metabolism, Pfizer Central Research, Groton, CT 06340, USA
    Drug Metab Dispos 25:1359-69. 1997
    ..Furthermore, the extent of nonspecific binding to microsomes is likely an important parameter to consider when attempting to relate Ki values measured in vitro to observations of drug-drug interactions (or the lack thereof) in vivo...
  11. ncbi request reprint Drug metabolism and drug interactions: application and clinical value of in vitro models
    Karthik Venkatakrishnan
    Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton, CT, USA
    Curr Drug Metab 4:423-59. 2003
    ....
  12. ncbi request reprint A comparison of 2-phenyl-2-(1-piperidinyl)propane (ppp), 1,1',1''-phosphinothioylidynetrisaziridine (thioTEPA), clopidogrel, and ticlopidine as selective inactivators of human cytochrome P450 2B6
    Robert L Walsky
    Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer, Inc, Groton, CT 06340, USA
    Drug Metab Dispos 35:2053-9. 2007
    ..Therefore, PPP can serve as a selective chemical inactivator of CYP2B6 and be used to define the role of CYP2B6 in the metabolism of drugs...
  13. ncbi request reprint Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes
    R S Obach
    Drug Metabolism Department, Candidate Synthesis, Enhancement, and Evaluation, Central Research Division, Pfizer, Inc, Groton, Connecticut 06340, USA
    Drug Metab Dispos 27:1350-9. 1999
    ..Overall, inclusion of both blood and microsome binding values gave the best agreement between in vivo clearance values and clearance values projected from in vitro intrinsic clearance data...
  14. ncbi request reprint (R)-, (S)-, and racemic fluoxetine N-demethylation by human cytochrome P450 enzymes
    J M Margolis
    Drug Metabolism Department, Candidate Synthesis, Enhancement, and Evaluation, Central Research Division, Pfizer Inc, Groton, Connecticut, USA
    Drug Metab Dispos 28:1187-91. 2000
    ..Together, these findings suggest a significant role for the polymorphically expressed CYP2D6 in fluoxetine clearance and are consistent with reports on the clinical pharmacokinetics of fluoxetine...
  15. ncbi request reprint A hybrid mixture discriminant analysis-random forest computational model for the prediction of volume of distribution of drugs in human
    Franco Lombardo
    Computational Chemistry and Scientific Computing Groups and Groton Non Clinical Statistics, Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut 06340, USA
    J Med Chem 49:2262-7. 2006
    ..The computational model described can predict human VD(ss) with an accuracy comparable to predictions requiring substantially greater effort and can be applied in place of animal experimentation...
  16. ncbi request reprint Selective inhibition of human cytochrome P4502C8 by montelukast
    Robert L Walsky
    Department of Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA
    Drug Metab Dispos 33:413-8. 2005
    ....
  17. ncbi request reprint Three-dimensional quantitative structure activity relationship computational approaches for prediction of human in vitro intrinsic clearance
    S Ekins
    Central Research Division, Pfizer Inc, Groton, Connecticut
    J Pharmacol Exp Ther 295:463-73. 2000
    ..These present models represent a preliminary application of QSAR software to modeling and prediction of human in vitro intrinsic clearance...
  18. doi request reprint In vitro metabolism and covalent binding of enol-carboxamide derivatives and anti-inflammatory agents sudoxicam and meloxicam: insights into the hepatotoxicity of sudoxicam
    R Scott Obach
    Pharmacokinetics, Dynamics, and Metabolism Department, Pfizer Global Research and Development, Groton, Connecticut, USA
    Chem Res Toxicol 21:1890-9. 2008
    ....
  19. doi request reprint A review of the clinical pharmacokinetics and pharmacodynamics of varenicline for smoking cessation
    Hélène M Faessel
    Clinical Pharmacology, Primary Care Unit, Pfizer Inc, New London, Connecticut 06320, USA
    Clin Pharmacokinet 49:799-816. 2010
    ..In all, the predictable pharmacokinetic properties and straightforward dispositional profile of varenicline simplify its use in clinical practice...
  20. doi request reprint 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
    R Scott Obach
    Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Global Research and Development, Groton, Connecticut 06340, USA
    Chem Res Toxicol 21:1814-22. 2008
    ....
  21. doi request reprint Comparison of metabolite profiles generated in Aroclor-induced rat liver and human liver subcellular fractions: considerations for in vitro genotoxicity hazard assessment
    R Scott Obach
    Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer, Inc, Groton, Connecticut 06340, USA
    Environ Mol Mutagen 49:631-41. 2008
    ....
  22. doi request reprint Prediction of drug-drug interactions from in vitro induction data: application of the relative induction score approach using cryopreserved human hepatocytes
    Odette A Fahmi
    Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Groton, Connecticut 06340, USA
    Drug Metab Dispos 36:1971-4. 2008
    ..This study demonstrates the general applicability of the relative induction score approach using the human cryopreserved hepatocyte model to predict clinical DDI...
  23. doi request reprint Trend analysis of a database of intravenous pharmacokinetic parameters in humans for 670 drug compounds
    R Scott Obach
    Pharmacokinetics Dynamics and Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut, USA
    Drug Metab Dispos 36:1385-405. 2008
    ....
  24. doi request reprint Physicochemical space for optimum oral bioavailability: contribution of human intestinal absorption and first-pass elimination
    Manthena V S Varma
    Pharmacokinetics Dynamics and Metabolism, Pfizer Global Research and Development, Pfizer Inc, Groton, Connecticut 06340, USA
    J Med Chem 53:1098-108. 2010
    ..This analysis may provide a rational judgment on the physicochemical space to optimize oral bioavailability...
  25. pmc Application of CYP3A4 in vitro data to predict clinical drug-drug interactions; predictions of compounds as objects of interaction
    Kuresh A Youdim
    Pfizer Global Research and Development, Department of Pharmacokinetics, Dynamics and Metabolism, Sandwich, Kent, UK
    Br J Clin Pharmacol 65:680-92. 2008
    ..Prediction of DDIs from in vitro data is commonly obtained using estimates of enzyme K(i), inhibitor and substrate concentrations and absorption rate for substrate and inhibitor...
  26. doi request reprint Pharmacokinetics, metabolism, and excretion of torcetrapib, a cholesteryl ester transfer protein inhibitor, in humans
    Deepak Dalvie
    Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, San Diego, California, USA
    Drug Metab Dispos 36:2185-98. 2008
    ..Subsequent oxidations lead to the major circulating and excretory metabolites M1 and M4...
  27. ncbi request reprint In vitro metabolism of CP-122,721 ((2S,3S)-2-phenyl-3-[(5-trifluoromethoxy-2-methoxy)benzylamino]piperidine), a non-peptide antagonist of the substance P receptor
    R Scott Obach
    Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Global Research and Development, Pfizer Inc, Groton, CT 06340, USA
    Drug Metab Pharmacokinet 22:336-49. 2007
    ..Combined, these findings provide a comprehensive understanding of the metabolism of this new agent...
  28. ncbi request reprint Lack of pharmacokinetic and pharmacodynamic interactions between a smoking cessation therapy, varenicline, and warfarin: an in vivo and in vitro study
    Aaron H Burstein
    PharmD, Pfizer Global Research and Development, Groton New London Labs, Eastern Point Road MS8260 2505, Groton, CT 06340, USA
    J Clin Pharmacol 47:1421-9. 2007
    ..Concomitant administration of varenicline and warfarin was well tolerated. Consequently, warfarin can be safely administered with varenicline without the need for dose adjustment...
  29. doi request reprint Metabolites: have we MIST out the importance of structure and physicochemistry?
    Dennis A Smith
    Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc, Sandwich, Kent, UK
    Bioanalysis 2:1223-33. 2010
    ..Assignment of clearance routes is facilitated by assessment of the proportion of parent drug cleared by the various routes using excreted metabolite data...
  30. ncbi request reprint Drug-drug interactions via mechanism-based cytochrome P450 inactivation: points to consider for risk assessment from in vitro data and clinical pharmacologic evaluation
    Karthik Venkatakrishnan
    Department of Clinical Pharmacology, Pfizer Global Research and Development, MS 8260 2626, Eastern Point Road, Groton, CT 06340, USA
    Curr Drug Metab 8:449-62. 2007
    ..The time course of reversal of DDI resulting from CYP inactivation is determined by the half-life of the enzyme which is an important consideration in the design and interpretation of clinical DDI studies with inactivators...
  31. ncbi request reprint Mechanism-based inactivation of cytochrome P450 enzymes: chemical mechanisms, structure-activity relationships and relationship to clinical drug-drug interactions and idiosyncratic adverse drug reactions
    Amit S Kalgutkar
    Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Global Research and Development, Groton, CT 06340, USA
    Curr Drug Metab 8:407-47. 2007
    ..In addition, the current state-of-the-art of the methodology used in predicting the magnitude of DDIs using in vitro P450 inactivation data and human pharmacokinetic parameters is discussed in detail...
  32. doi request reprint Clearing the MIST (metabolites in safety testing) of time: The impact of duration of administration on drug metabolite toxicity
    Dennis A Smith
    Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc, Sandwich, Kent, UK
    Chem Biol Interact 179:60-7. 2009
    ..The perceived risk of a unique human metabolite as a potential health risk by carcinogenesis becomes exceedingly low when the time scale for effect is compared with the age of patients undergoing therapy and their duration of treatment...
  33. doi request reprint Assessment of three human in vitro systems in the generation of major human excretory and circulating metabolites
    Deepak Dalvie
    Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Global Research and Development, San Diego, California 92121, USA
    Chem Res Toxicol 22:357-68. 2009
    ....
  34. ncbi request reprint Predicting drug-drug interactions from in vitro drug metabolism data: challenges and recent advances
    R Scott Obach
    Pfizer, Eastern Point Road, Groton, CT 06340, USA
    Curr Opin Drug Discov Devel 12:81-9. 2009
    ..The findings of research reported over the past few years to address these uncertainties regarding the use of in vitro data to predict DDI are discussed...
  35. doi request reprint Cross-species comparison of the metabolism and excretion of zoniporide: contribution of aldehyde oxidase to interspecies differences
    Deepak Dalvie
    Pfizer Global Research and Development, San Diego, California, USA
    Drug Metab Dispos 38:641-54. 2010
    ..No further evaluation of M2 was considered because it was detected only in the human fecal extracts. Hence, no further toxicological evaluation of the three human metabolites was undertaken...
  36. doi request reprint In vitro-in vivo correlation for intrinsic clearance for drugs metabolized by human aldehyde oxidase
    Michael Zientek
    Pharmacokinetics, Pharmacodynamics, and Drug Metabolism Pfizer Inc, La Jolla, California, USA
    Drug Metab Dispos 38:1322-7. 2010
    ....
  37. doi request reprint Effect of intestinal glucuronidation in limiting hepatic exposure and bioactivation of raloxifene in humans and rats
    Deepak Dalvie
    Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, San Diego, California 92121, USA
    Chem Res Toxicol 21:2260-71. 2008
    ....
  38. doi request reprint Metabolism of ramelteon in human liver microsomes and correlation with the effect of fluvoxamine on ramelteon pharmacokinetics
    R Scott Obach
    Pfizer, Inc, Groton, Connecticut 06340, USA
    Drug Metab Dispos 38:1381-91. 2010
    ..Nevertheless, the example of the fluvoxamine-ramelteon DDI offers a unique example wherein one drug can simultaneously inhibit multiple enzymatic pathways of a second drug...
  39. doi request reprint Physicochemical determinants of human renal clearance
    Manthena V S Varma
    Pharmacokinetics Dynamics and Metabolism, Pfizer Global Research and Development, Pfizer Inc, Groton, Connecticut, USA
    J Med Chem 52:4844-52. 2009
    ..These fundamental properties can be valuable in early prediction of human renal clearance and can aid the chemist in structural modifications to optimize drug disposition...
  40. doi request reprint Glycerolysis of acyl glucuronides as an artifact of in vitro drug metabolism incubations
    R Scott Obach
    Pfizer Inc, Groton, CT 06340, USA
    Drug Metab Dispos 37:1581-6. 2009
    ..The potential formation of glycerol esters of carboxylic acid drugs undergoing acyl glucuronidation in vitro represents an experimental artifact to which drug metabolism scientists should be aware...
  41. doi request reprint Comparison of different algorithms for predicting clinical drug-drug interactions, based on the use of CYP3A4 in vitro data: predictions of compounds as precipitants of interaction
    Odette A Fahmi
    Pfizer Global Research and Development, Groton, CT 06340, UA
    Drug Metab Dispos 37:1658-66. 2009
    ..59 and 1.47. From these findings it can be concluded that in vivo DDIs for CYP3A4 can be predicted from in vitro data, even when more than one biochemical phenomenon occurs simultaneously...
  42. doi request reprint A strategy for the risk assessment of human genotoxic metabolites
    Krista L Dobo
    Pfizer Global Research and Development, Drug Safety Research and Development, Genetic Toxicology, Groton, Connecticut 06340, USA
    Chem Res Toxicol 22:348-56. 2009
    ..Practical case examples are presented to illustrate the application of the risk assessment method within the context of drug development and to highlight its utility and limitations...
  43. doi request reprint Cytochrome P450 3A4 mRNA is a more reliable marker than CYP3A4 activity for detecting pregnane X receptor-activated induction of drug-metabolizing enzymes
    Odette A Fahmi
    Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Inc Global Research and Development, Eastern Point Road, Groton, CT 06340, USA
    Drug Metab Dispos 38:1605-11. 2010
    ..The best classification was observed when the cutoff criteria based on fold induction relative to the vehicle control, using mRNA data are used...
  44. doi request reprint Metabolites in safety testing (MIST): considerations of mechanisms of toxicity with dose, abundance, and duration of treatment
    Dennis A Smith
    Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc, Sandwich, Kent, UK
    Chem Res Toxicol 22:267-79. 2009
    ..The review also updates the enzymatic basis for the differences between species and how these relate to MIST considerations...
  45. doi request reprint A simple liquid chromatography-tandem mass spectrometry method to determine relative plasma exposures of drug metabolites across species for metabolite safety assessments
    Hongying Gao
    Pharmacokinetics, Dynamics and Metabolism, Pfizer, Inc, Groton, CT 06340, USA
    Drug Metab Dispos 38:2147-56. 2010
    ..A strategy for application of this approach within standard drug development processes is described...
  46. doi request reprint Can in vitro metabolism-dependent covalent binding data distinguish hepatotoxic from nonhepatotoxic drugs? An analysis using human hepatocytes and liver S-9 fraction
    Jonathon N Bauman
    Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Global Research and Development, Groton, Connecticut 06340, USA
    Chem Res Toxicol 22:332-40. 2009
    ..will be essential to any understanding of the problem of metabolism-dependent hepatotoxicity and predicting toxicity from in vitro experiments...
  47. doi request reprint A holistic strategy for characterizing the safety of metabolites through drug discovery and development
    Don Walker
    Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, United Kingdom
    Chem Res Toxicol 22:1653-62. 2009
    ....
  48. ncbi request reprint What is the objective of the mass balance study? A retrospective analysis of data in animal and human excretion studies employing radiolabeled drugs
    Sarah J Roffey
    Pharmacokinetics, Dynamics, and Metabolism, Pfizer, Inc, Sandwich, Kent, UK
    Drug Metab Rev 39:17-43. 2007
    ....
  49. ncbi request reprint Impact of nonspecific binding to microsomes and phospholipid on the inhibition of cytochrome P4502D6: implications for relating in vitro inhibition data to in vivo drug interactions
    Jeannine M Margolis
    Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut 06340, USA
    Drug Metab Dispos 31:606-11. 2003
    ..The implications of this on the prediction of drug-drug interactions from in vitro data are discussed...
  50. ncbi request reprint Metabolism and disposition of varenicline, a selective alpha4beta2 acetylcholine receptor partial agonist, in vivo and in vitro
    R Scott Obach
    Department of Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA
    Drug Metab Dispos 34:121-30. 2006
    ..The straightforward dispositional profile of varenicline should simplify its use in the clinic as an aid in smoking cessation...
  51. ncbi request reprint The utility of in vitro cytochrome P450 inhibition data in the prediction of drug-drug interactions
    R Scott Obach
    Pfizer Global Research and Development, Groton Laboratories, MS4088, Groton, CT 06340, USA
    J Pharmacol Exp Ther 316:336-48. 2006
    ..Overall, these findings support the conclusion that P450 in vitro inhibition data are valuable in designing clinical DDI study strategies and can be used to predict the magnitudes of DDI...
  52. ncbi request reprint Biotransformation of a GABAA receptor partial agonist in sprague-dawley rats and cynomolgus monkeys: identification of two unique N-carbamoyl metabolites
    Christopher L Shaffer
    Department of Pharmacokinetics, Pharmacodynamics and Metabolism, Pfizer Global Research and Development, Groton New London Laboratories, Pfizer Inc, Eastern Point Road, MS 4075, Groton, CT 06340, USA
    Drug Metab Dispos 33:1688-99. 2005
    ..It is proposed that M7 arises from an equilibrium between 1 and dissolved CO2-equivalents both in vivo and in vitro, similar to carbamino bonds observed in hemoglobin and certain amino acids, respectively...
  53. ncbi request reprint Seeing through the mist: abundance versus percentage. Commentary on metabolites in safety testing
    Dennis A Smith
    Pharmacokinetics, Dynamics, and Metabolism, Pfizer, Inc, Sandwich, Kent, UK CT13 9NJ
    Drug Metab Dispos 33:1409-17. 2005
    ..g., suprapharmacological effects, secondary pharmacological effects, nonspecific effects). Decision trees are described that can be used to address human metabolites in safety testing...
  54. ncbi request reprint A comprehensive listing of bioactivation pathways of organic functional groups
    Amit S Kalgutkar
    Pharmacokinetics, Dynamics and Metabolism Department, PGRD, Groton, CT 06340, USA
    Curr Drug Metab 6:161-225. 2005
    ....
  55. ncbi request reprint In vitro-in vivo extrapolation of CYP2D6 inactivation by paroxetine: prediction of nonstationary pharmacokinetics and drug interaction magnitude
    Karthik Venkatakrishnan
    Department of Clinical Pharmacokinetics and Pharmacodynamics, Pfizer Global Research and Development, Groton, CT 06340, USA
    Drug Metab Dispos 33:845-52. 2005
    ..In summary, the scaling model for mechanism-based inactivation successfully predicted the pharmacokinetic consequences of CYP2D6 inactivation by paroxetine from in vitro data...
  56. ncbi request reprint The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model
    Angela Doran
    Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA
    Drug Metab Dispos 33:165-74. 2005
    ..However, for such agents, unbound plasma concentrations may need to be greater than values projected using receptor affinity data to achieve adequate receptor occupancy for effect...
  57. ncbi request reprint Prediction of human volume of distribution values for neutral and basic drugs. 2. Extended data set and leave-class-out statistics
    Franco Lombardo
    Molecular Properties Group, Pfizer Global Research and Development, Groton Laboratories, Groton, Connecticut 06340, USA
    J Med Chem 47:1242-50. 2004
    ..The reduction in the use of animals and the overall faster and cheaper accessibility of the parameters used make this method highly attractive for prospectively predicting the VD of new chemical entities in humans...
  58. ncbi request reprint Reaction phenotyping in drug discovery: moving forward with confidence?
    J Andrew Williams
    Department of Pharmacokinetics, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA
    Curr Drug Metab 4:527-34. 2003
    ..Consequently, this data should be used to avoid costly late stage attrition...
  59. ncbi request reprint Prediction of volume of distribution values in humans for neutral and basic drugs using physicochemical measurements and plasma protein binding data
    Franco Lombardo
    Molecular Properties Group, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA
    J Med Chem 45:2867-76. 2002
    ..A discussion of the potential errors that may be encountered, including errors in the determination of f(u), is offered, and the caveats about the use of computed vs experimentally determined logD and pK(a) values are addressed...
  60. ncbi request reprint Mechanism-based inactivation of human recombinant P450 2C9 by the nonsteroidal anti-inflammatory drug suprofen
    John P O'Donnell
    Pharmacokinetics, Dynamics, and Metabolism, Pfizer Global Research and Development, Groton, CT 06340, USA
    Drug Metab Dispos 31:1369-77. 2003
    ..This electrophilic alpha, beta-unsaturated aldehyde represents a possible reactive intermediate that bioalkylates P450 2C9...
  61. ncbi request reprint Drug-drug interactions: an important negative attribute in drugs
    R Scott Obach
    Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA
    Drugs Today (Barc) 39:301-38. 2003
    ....
  62. ncbi request reprint Drugs that inhibit oxidation reactions catalyzed by aldehyde oxidase do not inhibit the reductive metabolism of ziprasidone to its major metabolite, S-methyldihydroziprasidone: an in vitro study
    R Scott Obach
    Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Pfizer Global Research and Development, Pfizer, Inc, Groton, CT 06340, USA
    J Clin Psychopharmacol 25:605-8. 2005
    ..Aldehyde oxidase oxidation and reduction reactions appear to have different sensitivities to inhibitors. These data suggest that it is unlikely that aldehyde oxidase inhibitors could cause increases in ziprasidone exposure in the clinic...
  63. ncbi request reprint In vitro cytochrome P450 inhibition data and the prediction of drug-drug interactions: qualitative relationships, quantitative predictions, and the rank-order approach
    R Scott Obach
    Department of Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories MS 4088, Groton, CT 06340, USA
    Clin Pharmacol Ther 78:582-92. 2005
  64. ncbi request reprint Effects of steady-state lasofoxifene on CYP2D6- and CYP2E1-mediated metabolism
    Robert A Moller
    Pfizer Worldwide Clinical Development, New York, NY 10017 5755, USA
    Ann Pharmacother 40:32-7. 2006
    ..Lasofoxifene, a selective estrogen receptor modulator, may be coadministered with other drugs, raising the issue of drug-drug interactions...
  65. ncbi request reprint Strategy for genotoxicity testing--metabolic considerations
    Warren W Ku
    Pfizer Global Research and Development, Drug Safety Research and Development, Groton, CT 06340, USA
    Mutat Res 627:59-77. 2007
    ....
  66. ncbi request reprint Evaluation of 227 drugs for in vitro inhibition of cytochrome P450 2B6
    Robert L Walsky
    Pfizer Global Research and Development, Groton New London Laboratories, Eastern Point Road, Groton, CT 06340, USA
    J Clin Pharmacol 46:1426-38. 2006
    ..These findings are discussed in context to potential drug interactions that could be observed between these agents and drugs for which CYP2B6 is involved in metabolism...
  67. ncbi request reprint Biotransformation reactions of five-membered aromatic heterocyclic rings
    Deepak K Dalvie
    Pharmacokinetics, Dynamics and Drug Metabolism, Pfizer Global Research and Development, Eastern Point Road, Groton, Connecticut 06340, USA
    Chem Res Toxicol 15:269-99. 2002
  68. ncbi request reprint Mechanism-based inactivation of human cytochrome p450 enzymes and the prediction of drug-drug interactions
    R Scott Obach
    Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer, Inc, Groton, CT 06340, USA
    Drug Metab Dispos 35:246-55. 2007
    ..Overall, these findings support the conclusion that P450 in vitro inactivation data are valuable in predicting clinical DDIs that can occur via this mechanism...
  69. ncbi request reprint Metabolism of nomifensine to a dihydroisoquinolinium ion metabolite by human myeloperoxidase, hemoglobin, monoamine oxidase A, and cytochrome P450 enzymes
    R Scott Obach
    Department of Pharmacokinetics, Dynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA
    Drug Metab Dispos 34:1310-6. 2006
    ..These findings suggest that the electrophilic nomifensine dihydroisoquinolinium metabolite, which can be generated by several enzymes, could be behind toxic responses to nomifensine such as hemolytic anemia and hepatotoxicity...
  70. ncbi request reprint Inhibition of human cytochrome P450 enzymes by constituents of St. John's Wort, an herbal preparation used in the treatment of depression
    R S Obach
    Drug Metabolism Department, Candidate Synthesis, Enhancement, and Evaluation, Central Research Division, Pfizer, Inc, Groton, Connecticut 06340, USA
    J Pharmacol Exp Ther 294:88-95. 2000
    ....
  71. ncbi request reprint Examination of 209 drugs for inhibition of cytochrome P450 2C8
    Robert L Walsky
    Pharmacokientics, Pharmacodynamics, and Drug Metabolism, Pfizer Global Research and Development, Groton New London Laboratories, Groton, CT 06340, USA
    J Clin Pharmacol 45:68-78. 2005
    ....
  72. ncbi request reprint Mechanism-based inactivation of human cytochrome P450 enzymes: strategies for diagnosis and drug-drug interaction risk assessment
    K Venkatakrishnan
    Clinical Pharmacology, Pfizer Global Research and Development, MS8260 2626, EasternPoint Road, Groton, CT 06340, USA
    Xenobiotica 37:1225-56. 2007
    ....
  73. ncbi request reprint The prediction of human clearance from hepatic microsomal metabolism data
    R S Obach
    Drug Metabolism Department, Pfizer Inc, Groton, CT 06340, USA
    Curr Opin Drug Discov Devel 4:36-44. 2001
    ....
  74. ncbi request reprint Expression and characterization of canine cytochrome P450 2D15
    F Roussel
    Drug Metabolism Department, Molecular Sciences Department, Pfizer Inc, Eastern Point Road, Groton, Connecticut 06340, USA
    Arch Biochem Biophys 357:27-36. 1998
    ..Thus, the dog expresses a CYP2D ortholog possessing enzymatic activities similar to human CYP2D6, but is affected by the inhibitors quinine and quinidine in a manner closer to that of rat CYP2D1...
  75. doi request reprint Metabolism, pharmacokinetics and excretion of the GABA(A) receptor partial agonist [(14)C]CP-409,092 in rats
    A Kamel
    Department of Pharmacokinetics, Pharmacodynamics and Metabolism, Pfizer Global Research and Development, Groton New London Laboratories, Pfizer, Inc, Groton, CT, USA
    Xenobiotica 40:400-14. 2010
    ....
  76. ncbi request reprint Effect of human renal cationic transporter inhibition on the pharmacokinetics of varenicline, a new therapy for smoking cessation: an in vitro-in vivo study
    B Feng
    Department of Pharmacokinetics, Pharmacodynamics, Drug Metabolism, Pfizer Global Research and Development, Groton, Connecticut, USA
    Clin Pharmacol Ther 83:567-76. 2008
    ..Consequently, it can be reasonably expected that other inhibitors of hOCT2 would not cause greater renal interactions with varenicline than that seen with the efficient hOCT2 inhibitor cimetidine...
  77. ncbi request reprint Microsomal protein concentration modifies the apparent inhibitory potency of CYP3A inhibitors
    Thanh Huu Tran
    Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and New England Medical Center, Boston, Massachusetts 02111, USA
    Drug Metab Dispos 30:1441-5. 2002
    ..The effect can be minimized by use of the lowest possible microsomal protein concentration for in vitro studies of metabolic inhibition...
  78. ncbi request reprint Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine
    Kirk M Bertelsen
    Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts 02111, USA
    Drug Metab Dispos 31:289-93. 2003
    ..These data are consistent with mechanism-based inhibition of CYP2D6 by paroxetine but not by quinidine or fluoxetine...
  79. ncbi request reprint The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective
    Thorir D Bjornsson
    Wyeth, Collegeville, Pennsylvania, USA
    Drug Metab Dispos 31:815-32. 2003
    ....
  80. ncbi request reprint Ziprasidone metabolism, aldehyde oxidase, and clinical implications
    Christine Beedham
    Department of Clinical Sciences, School of Life Sciences, University of Bradford, Bradford, West Yorkshire BD7 1DP, United Kingdom
    J Clin Psychopharmacol 23:229-32. 2003
    ..Consequently, it is unlikely that there would be any pharmacokinetic interaction between ethanol and ziprasidone...
  81. ncbi request reprint Impact of parallel pathways of drug elimination and multiple cytochrome P450 involvement on drug-drug interactions: CYP2D6 paradigm
    Kiyomi Ito
    School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Oxford Road, Manchester M13 9PL, UK
    Drug Metab Dispos 33:837-44. 2005
    ..It is concluded that incorporating parallel pathways provides a valuable step forward in making quantitative predictions of drug-drug interactions from in vitro data...
  82. doi request reprint 2-aryloxy-4-alkylaminopyridines: discovery of novel corticotropin-releasing factor 1 antagonists
    Yuhpyng L Chen
    Medicinal Chemistry Department, Pfizer, Inc, Groton, Connecticut 06340, USA
    J Med Chem 51:1385-92. 2008
    ..Compound 3a was advanced to the clinic. The synthesis of representative potential candidates and their in vitro, ex vivo, and in vivo data are described...
  83. ncbi request reprint Maximal inhibition of intestinal first-pass metabolism as a pragmatic indicator of intestinal contribution to the drug-drug interactions for CYP3A4 cleared drugs
    Aleksandra Galetin
    School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, UK
    Curr Drug Metab 8:685-93. 2007
    ....
  84. ncbi request reprint NADPH-dependent covalent binding of [3H]paroxetine to human liver microsomes and S-9 fractions: identification of an electrophilic quinone metabolite of paroxetine
    Sabrina X Zhao
    Pharmacokinetics, Dynamics and Metabolism Department, Pfizer Global Research and Development, Groton, Connecticut, USA
    Chem Res Toxicol 20:1649-57. 2007
    ....
  85. ncbi request reprint Metabolites and safety: What are the concerns, and how should we address them?
    Dennis A Smith
    Pharmacokinetics, Dynamics, and Drug Metabolism, Global Research and Development, Pfizer, Inc, Groton, Connecticut 06340, USA
    Chem Res Toxicol 19:1570-9. 2006
    ....
  86. ncbi request reprint Varenicline: new treatment with efficacy in smoking cessation
    Victor I Reus
    Department of Psychiatry, University of California School of Medicine, San Francisco, California 94143 0984, USA
    Drugs Today (Barc) 43:65-75. 2007
    ..Its targeted mechanism of action, superior efficacy and excellent tolerability make varenicline a welcome and useful addition to the therapeutic options for smoking cessation...
  87. ncbi request reprint Verification of the selectivity of (+)N-3-benzylnirvanol as a CYP2C19 inhibitor
    Robert L Walsky
    Drug Metab Dispos 31:343. 2003
  88. ncbi request reprint The time to move cytochrome p450 induction into mainstream pharmacology is long overdue
    Dennis A Smith
    Drug Metab Dispos 35:697-8. 2007