Research Topics
Species | TIMOTHY TRACYSummaryAffiliation: University of Minnesota Country: USA Publications
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Publications
Modeling kinetic data from in vitro drug metabolism enzyme experimentsTimothy S Tracy
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA
Drug Metab Rev 36:231-42. 2004..This article briefly summarizes the types of equations necessary to adequately model both typical and atypical kinetic profiles in order to facilitate correct estimation of the relevant kinetic parameters...
CYP2D6-CYP2C9 protein-protein interactions and isoform-selective effects on substrate binding and catalysisMurali Subramanian
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN 55126, USA
Drug Metab Dispos 37:1682-9. 2009..In summary, CYP2C9-CYP2D6 interactions can alter catalytic activity and, thus, influence in vitro-in vivo correlation predictions...- Atypical enzyme kinetics: their effect on in vitro-in vivo pharmacokinetic predictions and drug interactionsTimothy S Tracy
Dept of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, USA
Curr Drug Metab 4:341-6. 2003..Furthermore, potential, artifactual causes of atypical kinetic phenomena will be described... - Temporal changes in drug metabolism (CYP1A2, CYP2D6 and CYP3A Activity) during pregnancyTimothy S Tracy
Department of Experimental and Clinical Pharmacology and Center of Excellence in Women s Health, University of Minnesota, Minneapolis, Minn, USA
Am J Obstet Gynecol 192:633-9. 2005..The purpose of this study was to determine whether drug metabolism (CYP1A2, CYP2D6 and CYP3A) activity varies in the pregnant state compared with the nonpregnant state... - Atypical cytochrome p450 kinetics: implications for drug discoveryTimothy S Tracy
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA
Drugs R D 7:349-63. 2006..Thus, the clinical relevance of these phenomena remains inconclusive... - Activation of CYP2C9-mediated metabolism by a series of dapsone analogs: kinetics and structural requirementsJ Matthew Hutzler
Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, West Virginia 26506, USA
Drug Metab Dispos 30:1194-200. 2002..However, the effects of these analogs appear to be concentration- and substrate-dependent, further complicating the prediction of these types of in vitro interactions... - Polymorphic variants (CYP2C9*3 and CYP2C9*5) and the F114L active site mutation of CYP2C9: effect on atypical kinetic metabolism profilesTimothy S Tracy
Deparment of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, West Virginia 26506, USA
Drug Metab Dispos 30:385-90. 2002..It seems that the kinetic profile of CYP2C9-mediated metabolism is dependent on both substrate and the CYP2C9 allelic variant, thus having potential ramifications on drug disposition predictions made during the development process... - Visible spectra of type II cytochrome P450-drug complexes: evidence that "incomplete" heme coordination is commonCharles W Locuson
Department of Experimental and Clinical Pharmacology, University of Minnesota, College of Pharmacy, 7 115B Weaver Densford Hall, 308 Harvard Street SE, Minneapolis, MN 55455, USA
Drug Metab Dispos 35:614-22. 2007..Therefore, difference spectra may help reveal "weak" coordination to the heme that results from suboptimal orientation or ligand binding to more remote locations within the P450 active sites... - Inhibition of CYP2D6 activity by bupropionMichael Kotlyar
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Twin Cities Campus, Minneapolis, MN 55455, USA
J Clin Psychopharmacol 25:226-9. 2005..Bupropion is therefore a potent inhibitor of CYP2D6 activity, and care should be exercised when initiating or discontinuing bupropion use in patients taking drugs metabolized by CYP2D6... - Differential activation of CYP2C9 variants by dapsoneMatthew A Hummel
Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, USA
Biochem Pharmacol 67:1831-41. 2004..Thus, amino acid substitutions of CYP2C9 variants affect the degree of dapsone activation in a genotype-dependent fashion. Furthermore, the degree of effect noted across variants appeared to be dependent on the substrate studied... - Substrate proton to heme distances in CYP2C9 allelic variants and alterations by the heterotropic activator, dapsoneMatthew A Hummel
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 7 115B Weaver Densford Hall, 308 Harvard Street, SE, Minneapolis, MN 55455, USA
Arch Biochem Biophys 475:175-83. 2008.... - CYP2C9 protein interactions with cytochrome b(5): effects on the coupling of catalysisCharles W Locuson
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
Drug Metab Dispos 35:1174-81. 2007..Together, these findings suggest that cyt b5 can alter multiple steps in the P450 catalytic cycle via complex interactions with P450 and P450 reductase... - Correlation between bilirubin glucuronidation and estradiol-3-gluronidation in the presence of model UDP-glucuronosyltransferase 1A1 substrates/inhibitorsJin Zhou
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
Drug Metab Dispos 39:322-9. 2011..Thus, estradiol-3-glucuronidation can serve as a good surrogate for predicting inhibition of bilirubin glucuronidation with the caveat that occasionally compounds may demonstrate activation of estradiol-3-glucuronidation... - Differential genotype dependent inhibition of CYP2C9 in humansVikas Kumar
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
Drug Metab Dispos 36:1242-8. 2008..In summary, the presence of CYP2C9(*)3 alleles (either one or two alleles) can alter the degree of drug interaction observed upon coadministration of inhibitors... - Use of simple docking methods to screen a virtual library for heteroactivators of cytochrome P450 2C9Charles W Locuson
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA
J Med Chem 50:1158-65. 2007..One of the top-scoring compounds identified was verified to be a CYP2C9 heteroactivator in vitro, and it possessed activity similar to dapsone... - Studying cytochrome P450 kinetics in drug metabolismMelissa A Kramer
University of Minnesota, College of Pharmacy, Department of Experimental and Clinical Pharmacology, 7 115B Weaver Densford Hall, 308 Harvard Street SE, Minneapolis, MN 55455, USA
Expert Opin Drug Metab Toxicol 4:591-603. 2008.... - Enzyme source effects on CYP2C9 kinetics and inhibitionVikas Kumar
Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA
Drug Metab Dispos 34:1903-8. 2006..Considering these differences, consistent use of an enzyme source is an important component in producing comparable and reproducible kinetics and inhibition data with CYP2C9... - Amiodarone analog-dependent effects on CYP2C9-mediated metabolism and kinetic profilesVikas Kumar
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
Drug Metab Dispos 34:1688-96. 2006..In addition, these kinetics effects are concentration- and genotype-dependent... - CYP2C-catalyzed delta9-tetrahydrocannabinol metabolism: kinetics, pharmacogenetics and interaction with phenytoinTina M Bland
Department of Basic Pharmaceutical Sciences, School of Pharmacy, P.O. Box 9530, West Virginia University, 1 Medical Center Drive, Morgantown, WV 26506, USA
Biochem Pharmacol 70:1096-103. 2005..These in vitro data suggest the potential for an interaction from the concomitant administration of delta9-THC and phenytoin that could result in decreased phenytoin concentrations in vivo... - Preparation, characterization, and substrate metabolism of gold-immobilized cytochrome P450 2C9Peter M Gannett
Basic Pharmaceutical Sciences, West Virginia University, P O Box 9530, Morgantown, WV 26506, USA
J Am Chem Soc 128:8374-5. 2006..Most significantly, conditions that allow measurable CYP2C9 metabolism to occur have been developed... - CYP2C9 genotype-dependent effects on in vitro drug-drug interactions: switching of benzbromarone effect from inhibition to activation in the CYP2C9.3 variantMatthew A Hummel
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 308 Harvard St, S.E, Minneapolis, MN 55455, USA
Mol Pharmacol 68:644-51. 2005..3 not only reduces metabolism compared with CYP2C9.1 but can also dramatically alter inhibitor effects, suggesting that differential degrees of drug inhibition interactions may occur in individuals with this variant form of CYP2C9... - Atypical kinetic profiles in drug metabolism reactionsJ Matthew Hutzler
Department of Basic Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, West Virginia 26506, USA
Drug Metab Dispos 30:355-62. 2002 - Polymorphic variants of CYP2C9: mechanisms involved in reduced catalytic activityLian Wei
Department of Experimental and Clinical Pharmacology, University of Minnesota, 308 Harvard St SE, Minneapolis, MN 55455, USA
Mol Pharmacol 72:1280-8. 2007..These results suggest that in addition to coupling differences, differential uncoupling to shunt products and differences in spin state help explain the reduced catalytic activity in these enzymes... - Epoxidation of the methamphetamine pyrolysis product, trans-phenylpropene, to trans-phenylpropylene oxide by CYP enzymes and stereoselective glutathione adduct formationMadhu Sanga
Department of Basic Pharmaceutical Sciences, West Virginia University, 1 Medical Center Drive, Morgantown, WV 26506, USA
Toxicol Appl Pharmacol 211:148-56. 2006..Exposure of cultured C6 glial cells to (S,S)-phenylpropylene oxide produced a cytotoxic response in a concentration-dependent manner based on cell degeneration and death... - Influence of fluorescent probe size and cytochrome b5 on drug-drug interactions in CYP2C9Matthew A Hummel
Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, USA
J Biomol Screen 11:303-9. 2006..These results illustrate that multiple substrate probes may be necessary for screening drug-drug interaction in CYP2C9 and that cyt b5 effects can impart steric restraints on the CYP2C9 active site... - Heteroactivator effects on the coupling and spin state equilibrium of CYP2C9Charles W Locuson
University of Minnesota, Department of Experimental and Clinical Pharmacology, USA
Arch Biochem Biophys 449:115-29. 2006.... - CYP2C9 inhibition: impact of probe selection and pharmacogenetics on in vitro inhibition profilesVikas Kumar
Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA
Drug Metab Dispos 34:1966-75. 2006..Thus, both genotype and choice of probe substrate must be considered when attempting to predict potential CYP2C9 drug-drug interactions from in vitro data... - Glucuronidation of dihydrotestosterone and trans-androsterone by recombinant UDP-glucuronosyltransferase (UGT) 1A4: evidence for multiple UGT1A4 aglycone binding sitesJin Zhou
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA
Drug Metab Dispos 38:431-40. 2010..Our results suggest that multiple aglycone binding sites exist within UGT1A4, which may result in atypical kinetics (both homotropic and heterotropic) in a substrate-dependent fashion... - Electrocatalytic drug metabolism by CYP2C9 bonded to a self-assembled monolayer-modified electrodeMingli Yang
West Virginia University, Basic Pharmaceutical Sciences, Morgantown, WV 26506 9530, USA
Drug Metab Dispos 37:892-9. 2009..Furthermore, this system may provide a unique platform for both studying P450 enzyme electrochemistry and as a bioreactor to produce metabolites without the need for expensive redox transfer proteins and cofactors... - Induction and inhibition of cytochromes P450 by the St. John's wort constituent hyperforin in human hepatocyte culturesBernard J Komoroski
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA 15261, USA
Drug Metab Dispos 32:512-8. 2004.... - Identification of binding sites of non-I-helix water molecules in mammalian cytochromes p450Charles W Locuson
Department of Experimental and Clinical Pharmacology, University of Minnesota, College of Pharmacy, Minneapolis, Minnesota, USA
Drug Metab Dispos 34:1954-7. 2006.... - Alterations in drug disposition during pregnancy: implications for drug therapyLucy S Hodge
University of Minnesota, Department of Experimental and Clinical Pharmacology, College of Pharmacy, Minneapolis, MN 55455, USA
Expert Opin Drug Metab Toxicol 3:557-71. 2007..As such, pregnant women may require different dosing regimens than both men and non-pregnant women... - CYP2C9-CYP3A4 protein-protein interactions: role of the hydrophobic N terminusMurali Subramanian
Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55126, USA
Drug Metab Dispos 38:1003-9. 2010..These results show that the N-terminal membrane binding domains of CYP2C9 and CYP3A4 are involved in heteromer complex formation and that at least one consequence is a reduction in CYP2C9 activity... - Validation of incorporating flurbiprofen into the Pittsburgh cocktailNathalie K Zgheib
Center for Clinical Pharmacology, University of Pittsburgh, Pittsburgh, PA 15219-3138, USA
Clin Pharmacol Ther 80:257-63. 2006.... - Activation of cytochrome P450 2C9-mediated metabolism: mechanistic evidence in support of kinetic observationsJ Matthew Hutzler
Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy, Health Sciences Center, HSN, Morgantown, WV 26506, USA
Arch Biochem Biophys 410:16-24. 2003.... - Effector-mediated alteration of substrate orientation in cytochrome P450 2C9Matthew A Hummel
Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, West Virginia 26506, USA
Biochemistry 43:7207-14. 2004..Shift of the 4' proton of flurbiprofen closer to the heme iron of CYP2C9 in the presence of dapsone may play a role in activation...
Research Grants
- P450 Protein-Protein Interactions Determined by Selective Protein ManipulationTIMOTHY TRACY; Fiscal Year: 2009..abstract_text> ..
- Pharmacogenetics and Drug InteractionsTIMOTHY TRACY; Fiscal Year: 2007..these studies will permit a better understanding of drug inhibition potential in different P450 genotypes and serve as a foundation for increasing our understanding of interindividual differences in susceptibility to drug interactions ..
- Mechanisms of Atypical Drug Kinetics and InteractionsTIMOTHY TRACY; Fiscal Year: 2007..From these data, computer models will be developed to predict the occurrence of atypical kinetics and potential drug interactions to assist in the drug development process. ..
- PharmGKB Experimental Biology Workshop 2005TIMOTHY TRACY; Fiscal Year: 2005....
- Mechanisms of Atypical Drug Kinetics and InteractionsTIMOTHY TRACY; Fiscal Year: 2003..Additionally, in vivo studies of a CYP2C9 substrate and a known (in vitro) effector will be conducted. Taken together, these results will improve CYP2C9 in vitro-in vivo predictive capabilities. ..
- Pharmacogenetics and Drug InteractionsTIMOTHY TRACY; Fiscal Year: 2009..Improved understanding of these genetic changes and their effects on drug disposition will lead to improved drug therapy and better management of drug-drug interactions. ..