Opioids in Cancer Pain & Drug Abuse: Optimizing Therapy

Summary

Principal Investigator: Evan Kharasch
Affiliation: Washington University School of Medicine
Country: USA
Abstract: The overall objective of this renewal application is to sustain and expand the PI's patient-oriented research program in the pharmacology of opioids and HIV/AIDS drugs, specifically directed towards the therapy of substance abuse and pain. A principal component of this program will be the development of beginning clinical investigators. The specific research objectives are to 1) continue existing research which investigates mechanisms of variability in human opioid disposition, pharmacodynamics and clinical efficacy, and endeavors to optimize opioid therapy of substance abuse and cancer pain, 2) expand existing research on the mechanism of drug interactions with HIV/AIDS drugs and their clinical consequence, 3) facilitate program expansion into underutilized therapies such as nonsteroidal antiinflammatory drugs, and 4) mentor beginning clinical investigators in patient-oriented research, utilizing the above framework to spawn independent research programs. A critical focus will be interfacing in vitro and in vivo aspects of human drug disposition and efficacy, and translating recent discoveries in basic enzymology and pharmacogenetics of drug disposition into clinical strategies for optimized therapy. Methadone maintenance is the cornerstone of opiate abuse therapy, a vital and effective strategy for HTV/AIDS risk reduction, and widely used for cancer pain treatment. Methadone is characterized by extreme, unexplained, and unpredictable interindividual pharmacokinetic variability, causing inadequate pain treatment, opioid abstinence syndrome, treatment failures, and unwanted side effects. Methadone is metabolized by hepatic and intestinal cytochrome P450, and is a substrate for transporters in the intestine, brain, and kidney. Mechanism(s) of individual variability in methadone metabolism and transport are, however, unknown, as are their clinical consequences. Highly active antiretroviral therapy (HAART) is the cornerstone HIV/AIDS treatment, yet HIV/AIDS drugs cause profound, complex, and poorly understood drug interactions. To address these questions, experiments in vitro will use human liver and intestinal microsomes and transfected cell lines to identify relevant P450 isoforms and transporters and probe drug-drug interactions. Complementary clinical investigations will verify these identifications and establish the mechanism of HTV/AIDS drug interactions, and the influence of drug interactions and pharmacogenetics on opioid disposition and pharmacologic effects. Successful identification of the factors affecting metabolism, clearance, and clinical effects of methadone will improve the clinical outcome and reduce the costs of opiate addiction and cancer pain treatment. Successful identification of the mechanism of HIV/AIDS drug interactions will improve the therapy of HIV/AIDS.
Funding Period: 1999-05-01 - 2010-03-31
more information: NIH RePORT

Top Publications

  1. pmc High-sensitivity analysis of buprenorphine, norbuprenorphine, buprenorphine glucuronide, and norbuprenorphine glucuronide in plasma and urine by liquid chromatography-mass spectrometry
    Karen J Regina
    Department of Anesthesiology, Division of Clinical and Translational Research, Washington University in St Louis, St Louis, MO, United States
    J Chromatogr B Analyt Technol Biomed Life Sci 939:23-31. 2013
  2. pmc Estimation of the contribution of norketamine to ketamine-induced acute pain relief and neurocognitive impairment in healthy volunteers
    Erik Olofsen
    Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
    Anesthesiology 117:353-64. 2012
  3. pmc P-glycoprotein is a major determinant of norbuprenorphine brain exposure and antinociception
    Sarah M Brown
    Department of Pediatrics, Washington University in St Louis, St Louis, MO 63110, USA
    J Pharmacol Exp Ther 343:53-61. 2012
  4. pmc Role of cytochrome P4502B6 in methadone metabolism and clearance
    Evan D Kharasch
    Department of Anesthesiology, Division of Clinical and Translational Research, Washington University in St Louis, St Louis, MO, USA
    J Clin Pharmacol 53:305-13. 2013
  5. pmc A meta-analysis of CYP2D6 metabolizer phenotype and metoprolol pharmacokinetics
    C M Blake
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri, USA
    Clin Pharmacol Ther 94:394-9. 2013
  6. pmc Mechanism of autoinduction of methadone N-demethylation in human hepatocytes
    Scott D Campbell
    Department of Anesthesiology, Washington University in St Louis, 660 S Euclid Ave, Campus Box 8054, St Louis, MO 63110 1093, USA
    Anesth Analg 117:52-60. 2013
  7. pmc Cyclosporine-inhibitable blood-brain barrier drug transport influences clinical morphine pharmacodynamics
    Konrad Meissner
    Associate Professor of Anesthesiology, Universitätsmedizin Greifswald, Klinik für Anästhesiologie und Intensivmedizin, Greifswald, Germany, and Department of Anesthesiology, Division of Clinical and Translational Research, Washington University in St Louis, St Louis, Missouri Associate Professor of Anesthesiology, Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois Research Technician, Clinical Research Coordinator, Head Research Nurse, Department of Anesthesiology, Washington University in St Louis Russell D and Mary B Shelden Professor of Anesthesiology, Professor of Biochemistry and Molecular Biophysics, Vice Chancellor for Research, Departments of Anesthesiology and Biochemistry and Molecular Biophysics, Division of Clinical and Translational Research, Washington University in St Louis
    Anesthesiology 119:941-53. 2013
  8. pmc Significance of lipid composition in a blood-brain barrier-mimetic PAMPA assay
    Scott D Campbell
    1Department of Anesthesiology, Division of Clinical and Translational Research, Washington University in St Louis, St Louis, MO, USA
    J Biomol Screen 19:437-44. 2014
  9. pmc Sensitivity of intravenous and oral alfentanil and pupillary miosis as minimal and noninvasive probes for hepatic and first-pass CYP3A induction
    E D Kharasch
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St Louis, St Louis, Missouri, USA
    Clin Pharmacol Ther 90:100-8. 2011
  10. pmc Effect of rifampicin on S-ketamine and S-norketamine plasma concentrations in healthy volunteers after intravenous S-ketamine administration
    Ingeborg Noppers
    Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
    Anesthesiology 114:1435-45. 2011

Scientific Experts

  • Evan Kharasch
  • Todd J Schwedt
  • Kristine R Crews
  • Peter Nagele
  • Joseph Bloom
  • S Ekins
  • Robert Douglas Bruce
  • Brian J Kirby
  • Scott D Campbell
  • Sarah M Brown
  • Dale Whittington
  • Kenneth E Thummel
  • Karen J Regina
  • Jinda Fan
  • Thomas Kim
  • Jashvant D Unadkat
  • Rheem A Totah
  • Rebecka Coles
  • Konrad Meissner
  • Erik Olofsen
  • Pamela Sheffels
  • Ingeborg Noppers
  • Ann C Collier
  • Theresa Mariero Klees
  • C M Blake
  • Amanda Crafford
  • Jane Blood
  • Leon Aarts
  • Albert Dahan
  • Elise Sarton
  • Marieke Niesters
  • Amy London
  • Zhude Tu
  • Anshuman Sharma
  • Michael C Montana
  • I E Templeton
  • Brian Kirby
  • Bojan Lalovic
  • Kent L Kunze
  • Harshvardhan N Chaobal
  • Gregory Dembo
  • M Schwab
  • Michael J Avram
  • Viktar Yermolenka
  • Brian L Williamson
  • Amber M Francis
  • Michael J Holtzman
  • Danielle Tallchief
  • MICHAEL HOLTZMAN
  • Robert H Mach
  • Vaishali Dixit
  • Shihong Li
  • Rene Mooren
  • Pankaj Desai
  • Gregory G Gaehle
  • Andrei D Stefanescu
  • Kristi K Stubbert
  • Robert W Gereau
  • Laura F Cavallone
  • Kenneth Thummel
  • W L Nelson
  • K E Thummel
  • C Hoffer
  • K L Kunze
  • TONI ROBERTS
  • N Isoherranen
  • Kyle E Allen
  • Danny D Shen
  • Vishal S Narang
  • Christine J Hoffer
  • Lee Yuan Liu-Chen
  • Kenneth T Thummel
  • Nina Isoherranen
  • Wendel L Nelson
  • Christine Hoffer
  • Linda Risler
  • Sang B Park
  • Ola Dale

Detail Information

Publications53

  1. pmc High-sensitivity analysis of buprenorphine, norbuprenorphine, buprenorphine glucuronide, and norbuprenorphine glucuronide in plasma and urine by liquid chromatography-mass spectrometry
    Karen J Regina
    Department of Anesthesiology, Division of Clinical and Translational Research, Washington University in St Louis, St Louis, MO, United States
    J Chromatogr B Analyt Technol Biomed Life Sci 939:23-31. 2013
    ..Interassay precision and accuracy was within 10% for all four analytes in plasma and within 15% in urine. The method was applicable to pharmacokinetic studies of low-dose buprenorphine. ..
  2. pmc Estimation of the contribution of norketamine to ketamine-induced acute pain relief and neurocognitive impairment in healthy volunteers
    Erik Olofsen
    Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
    Anesthesiology 117:353-64. 2012
    ..One approach to assess the ketamine and norketamine contributions is by measuring the ketamine effect at varying ketamine and norketamine plasma concentrations using the CYP450 inducer rifampicin...
  3. pmc P-glycoprotein is a major determinant of norbuprenorphine brain exposure and antinociception
    Sarah M Brown
    Department of Pediatrics, Washington University in St Louis, St Louis, MO 63110, USA
    J Pharmacol Exp Ther 343:53-61. 2012
    ..Results show that norbuprenorphine is an in vitro and in vivo substrate of P-glycoprotein. P-glycoprotein-mediated efflux influences brain access and antinociceptive, but not the respiratory, effects of norbuprenorphine...
  4. pmc Role of cytochrome P4502B6 in methadone metabolism and clearance
    Evan D Kharasch
    Department of Anesthesiology, Division of Clinical and Translational Research, Washington University in St Louis, St Louis, MO, USA
    J Clin Pharmacol 53:305-13. 2013
    ..CYP2B6 inhibition reduces methadone N-demethylation and clearance, and alters methadone concentrations, demonstrating an important role for CYP2B6 in clinical methadone disposition...
  5. pmc A meta-analysis of CYP2D6 metabolizer phenotype and metoprolol pharmacokinetics
    C M Blake
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri, USA
    Clin Pharmacol Ther 94:394-9. 2013
    ..This study demonstrates a marked effect of CYP2D6 metabolizer phenotype on metoprolol pharmacokinetics and confirms enantiomer-specific metabolism of metoprolol...
  6. pmc Mechanism of autoinduction of methadone N-demethylation in human hepatocytes
    Scott D Campbell
    Department of Anesthesiology, Washington University in St Louis, 660 S Euclid Ave, Campus Box 8054, St Louis, MO 63110 1093, USA
    Anesth Analg 117:52-60. 2013
    ..In this investigation, we determined mechanism(s) of methadone autoinduction using human hepatocytes...
  7. pmc Cyclosporine-inhibitable blood-brain barrier drug transport influences clinical morphine pharmacodynamics
    Konrad Meissner
    Associate Professor of Anesthesiology, Universitätsmedizin Greifswald, Klinik für Anästhesiologie und Intensivmedizin, Greifswald, Germany, and Department of Anesthesiology, Division of Clinical and Translational Research, Washington University in St Louis, St Louis, Missouri Associate Professor of Anesthesiology, Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois Research Technician, Clinical Research Coordinator, Head Research Nurse, Department of Anesthesiology, Washington University in St Louis Russell D and Mary B Shelden Professor of Anesthesiology, Professor of Biochemistry and Molecular Biophysics, Vice Chancellor for Research, Departments of Anesthesiology and Biochemistry and Molecular Biophysics, Division of Clinical and Translational Research, Washington University in St Louis
    Anesthesiology 119:941-53. 2013
    ..Morphine, a drug with delayed clinical onset, is a substrate for the efflux transporter P-glycoprotein in vitro and in animals. This investigation tested whether morphine is a transporter substrate in humans...
  8. pmc Significance of lipid composition in a blood-brain barrier-mimetic PAMPA assay
    Scott D Campbell
    1Department of Anesthesiology, Division of Clinical and Translational Research, Washington University in St Louis, St Louis, MO, USA
    J Biomol Screen 19:437-44. 2014
    ..Lipid composition markedly influences passive permeability. This was most apparent for charged or bulky compounds. These results demonstrate the importance of using species-specific lipid models in passive permeability assays. ..
  9. pmc Sensitivity of intravenous and oral alfentanil and pupillary miosis as minimal and noninvasive probes for hepatic and first-pass CYP3A induction
    E D Kharasch
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St Louis, St Louis, Missouri, USA
    Clin Pharmacol Ther 90:100-8. 2011
    ..Single ALF concentrations detected all CYP3A induction, whereas MDZ was less sensitive. ALF miosis detected induction of first-pass but not hepatic CYP3A...
  10. pmc Effect of rifampicin on S-ketamine and S-norketamine plasma concentrations in healthy volunteers after intravenous S-ketamine administration
    Ingeborg Noppers
    Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
    Anesthesiology 114:1435-45. 2011
    ..The aim of this study was to investigate the effect of CYP enzyme induction by rifampicin on the pharmacokinetics of S-ketamine and its major metabolite, S-norketamine, in healthy volunteers...
  11. pmc Complex drug interactions of HIV protease inhibitors 1: inactivation, induction, and inhibition of cytochrome P450 3A by ritonavir or nelfinavir
    Brian J Kirby
    Department of Pharmaceutics, University of Washington, Seattle, WA, USA
    Drug Metab Dispos 39:1070-8. 2011
    ..The magnitude of these DDIs was more accurately predicted using PI CYP3A inactivation parameters generated in sandwich-cultured human hepatocytes rather than human liver microsomes...
  12. pmc Complex drug interactions of the HIV protease inhibitors 3: effect of simultaneous or staggered dosing of digoxin and ritonavir, nelfinavir, rifampin, or bupropion
    Brian J Kirby
    Department of Pharmaceutics, University of Washington, Seattle, Washington 98195, USA
    Drug Metab Dispos 40:610-6. 2012
    ..In summary, RTV or NFV do not induce P-glycoprotein activity measured with DIG, and RIF does so only under staggered administration...
  13. pmc Headache outcomes following treatment of unruptured intracranial aneurysms: a prospective analysis
    Todd J Schwedt
    Washington University School of Medicine, USA
    Cephalalgia 31:1082-9. 2011
    ..To analyze headache patterns prior to and following treatment of unruptured intracranial aneurysms and identify factors associated with different headache outcomes...
  14. pmc Simultaneous determination of alfentanil and midazolam in human plasma using liquid chromatography and tandem mass spectrometry
    Thomas Kim
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St Louis, St Louis, MO 63110, United States
    J Pharm Biomed Anal 55:487-93. 2011
    ..The procedure was validated and applied to the analysis of plasma samples from healthy human subjects administered oral and intravenous alfentanil and midazolam...
  15. pmc Concurrent assessment of hepatic and intestinal cytochrome P450 3A activities using deuterated alfentanil
    E D Kharasch
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St Louis, St Louis, Missouri, USA
    Clin Pharmacol Ther 89:562-70. 2011
    ..simultaneous dosing. These results show that concurrent administration of oral deuterated and i.v. ALF, either sequentially or simultaneously, is an efficient and effective approach to assessing hepatic and intestinal CYP3A activity...
  16. pmc The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European-Americans
    Joseph Bloom
    Department of Psychiatry, Washington University School of Medicine, Saint Louis, Missouri, USA
    Pharmacogenet Genomics 21:403-16. 2011
    ..To study the association between cytochrome P450 2A6 (CYP2A6) genotype and metabolism of nicotine to cotinine, identify functional polymorphisms, and develop a predictive genetic model of nicotine metabolism...
  17. pmc Nitrous oxide anesthesia and plasma homocysteine in adolescents
    Peter Nagele
    Department of Anesthesiology, Washington University, St Louis, MO, USA
    Anesth Analg 113:843-8. 2011
    ..Prolonged exposure to nitrous oxide can lead to neuropathy, spinal cord degeneration, and even death in children. We tested the hypothesis that nitrous oxide anesthesia causes a significant increase in plasma tHcy in children...
  18. pmc Complex drug interactions of HIV protease inhibitors 2: in vivo induction and in vitro to in vivo correlation of induction of cytochrome P450 1A2, 2B6, and 2C9 by ritonavir or nelfinavir
    Brian J Kirby
    Department of Pharmaceutics, University of Washington, Seattle, WA, USA
    Drug Metab Dispos 39:2329-37. 2011
    ....
  19. pmc Buprenorphine metabolites, buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically active
    Sarah M Brown
    Department of Pathology and Immunology, Washington University in St Louis, St Louis, Missouri 63110, USA
    Anesthesiology 115:1251-60. 2011
    ..Buprenorphine glucuronide metabolites pharmacology is undefined. This investigation determined binding and pharmacologic activity of the two glucuronide metabolites, and in comparison with buprenorphine and norbuprenorphine...
  20. pmc Perioperative pharmacokinetics of methadone in adolescents
    Anshuman Sharma
    Department of Anesthesiology, Washington University in St Louis, St Louis, Missouri 63110, USA
    Anesthesiology 115:1153-61. 2011
    ..The purpose of this investigation was to determine the pharmacokinetics of intravenous methadone in children undergoing surgery. Perioperative opioid-sparing effects were also assessed...
  21. pmc Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype
    K R Crews
    Department of Pharmaceutical Sciences, St Jude Children s Research Hospital, Memphis, Tennessee, USA
    Clin Pharmacol Ther 91:321-6. 2012
    ..The purpose of this guideline (periodically updated at http://www.pharmgkb.org) is to provide information relating to the interpretation of CYP2D6 genotype test results to guide the dosing of codeine...
  22. pmc Lack of indinavir effects on methadone disposition despite inhibition of hepatic and intestinal cytochrome P4503A (CYP3A)
    Evan D Kharasch
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St Louis, St Louis, Missouri 63110 1093, USA
    Anesthesiology 116:432-47. 2012
    ....
  23. pmc Mechanism of efavirenz influence on methadone pharmacokinetics and pharmacodynamics
    E D Kharasch
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St Louis, St Louis, Missouri, USA
    Clin Pharmacol Ther 91:673-84. 2012
    ..Methadone disposition was most consistent with efavirenz induction of hepatic CYP2B6-mediated methadone N-demethylation. Efavirenz may alter methadone pharmacodynamics...
  24. pmc Automated radiosynthesis of [11C]morphine for clinical investigation
    Jinda Fan
    Department of Radiology, Washington University School of Medicine, 510 South Kingshighway Blvd St Louis, MO 63110, USA
    Appl Radiat Isot 69:431-5. 2011
    ..Radiosynthesis took 45 min with a radiochemical yield ranging from 45% to 50% and specific activity ranging from 20 to 26 Ci/μmol (decay corrected to end-of-bombardment); radiochemical and chemical purities were >95% (n=28)...
  25. pmc Episodic and chronic migraineurs are hypersensitive to thermal stimuli between migraine attacks
    Todd J Schwedt
    Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA
    Cephalalgia 31:6-12. 2011
    ..To determine if migraineurs have evidence of interictal cutaneous sensitisation...
  26. pmc Chemical and enzyme-assisted syntheses of norbuprenorphine-3-β-D-glucuronide
    Jinda Fan
    Department of Radiology, Washington University in St Louis, 660 S Euclid Avenue, St Louis, Missouri 63110, United States
    Bioconjug Chem 22:752-8. 2011
    ..The fractional yield of the enzyme-assisted synthesis was greater than that of the chemical synthesis (67% vs 5.3%), but due to larger reaction volumes, the chemical synthesis afforded greater amounts of total 1...
  27. ncbi Enantiomeric metabolic interactions and stereoselective human methadone metabolism
    Rheem A Totah
    Department of Medicinal Chemistry, University of Washington Seattle, Washington, USA
    J Pharmacol Exp Ther 321:389-99. 2007
    ..In vivo, CYP2B6 may be a major determinant of methadone metabolism and disposition, and CYP2B6 activity and stereoselective metabolic interactions may confer variability in methadone disposition...
  28. ncbi Pharmacokinetic interactions between buprenorphine and antiretroviral medications
    R Douglas Bruce
    Yale University AIDS Program, New Haven, CT 06511, USA
    Clin Infect Dis 43:S216-23. 2006
    ..Review of the current state of knowledge regarding specific interactions between buprenorphine and antiretrovirals is followed by a review of the clinical applicability of these interactions...
  29. ncbi Simultaneous measurement of in vivo P-glycoprotein and cytochrome P450 3A activities
    Brian Kirby
    Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, WA 98195 7610, USA
    J Clin Pharmacol 46:1313-9. 2006
    ..Coadministration of digoxin and midazolam can be used to simultaneously phenotype P-gp and CYP3A activity without a significant pharmacokinetic interaction...
  30. ncbi Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: role of circulating active metabolites
    Bojan Lalovic
    Department of Pharmaceutics, University of Washington, Seattle 98195, USA
    Clin Pharmacol Ther 79:461-79. 2006
    ....
  31. ncbi Stereochemical aspects of itraconazole metabolism in vitro and in vivo
    Kent L Kunze
    Department of Pharmaceutics, H272 Health Sciences Building, Box 357610, University of Washington, Seattle, WA 98195, USA
    Drug Metab Dispos 34:583-90. 2006
    ..However, stereoselective elimination was diminished after multiple dosing, presumably as a result of CYP3A4 autoinhibition. In conclusion, the metabolism of ITZ is highly stereoselective in vitro and in vivo...
  32. ncbi Single-point sampling for assessment of constitutive, induced, and inhibited cytochrome P450 3A activity with alfentanil or midazolam
    Harshvardhan N Chaobal
    Departments of Anesthesiology and Medicinal Chemistry, University of Washington, 660 South Euclid Avenue, St Louis, MO 63110 1093, USA
    Clin Pharmacol Ther 78:529-39. 2005
    ..This investigation tested the hypothesis that a single concentration measurement can accurately predict alfentanil clearance and compared limited sampling results for alfentanil and midazolam...
  33. ncbi Paradoxical role of cytochrome P450 3A in the bioactivation and clinical effects of levo-alpha-acetylmethadol: importance of clinical investigations to validate in vitro drug metabolism studies
    Evan D Kharasch
    Department of Anesthesiology, University of Washington, Seattle, Washington 98195, USA
    Clin Pharmacokinet 44:731-51. 2005
    ..It also related changes in LAAM disposition during enzyme inhibition or induction to any changes in pharmacological effect...
  34. ncbi Pharmacogenetic determinants of human liver microsomal alfentanil metabolism and the role of cytochrome P450 3A5
    Theresa Mariero Klees
    Norwegian University of Science and Technology, Trondheim, Norway
    Anesthesiology 102:550-6. 2005
    ..This investigation tested the hypothesis that alfentanil is a substrate for CYP3A5 and that CYP3A5 pharmacogenetic variability influences human liver alfentanil metabolism...
  35. ncbi Central nervous system concentrations of cyclooxygenase-2 inhibitors in humans
    Gregory Dembo
    Department of Anesthesiology, University of Washington, Seattle, USA
    Anesthesiology 102:409-15. 2005
    ..Nevertheless, it remains unknown whether or which coxibs reach the CNS in humans. This investigation determined whether coxibs can reach the CNS in humans, based on CSF concentrations...
  36. ncbi Evaluation of first-pass cytochrome P4503A (CYP3A) and P-glycoprotein activities using alfentanil and fexofenadine in combination
    Evan D Kharasch
    Department of Anesthesiology, Box 356540, University of Washington, 1959 NE Pacific Street RR 442, Seattle, WA 98195, USA
    J Clin Pharmacol 45:79-88. 2005
    ..Alfentanil and fexofenadine in combination appear to be a useful probe for evaluating both first-pass CYP3A and P-gp activities in humans...
  37. pmc Contribution of itraconazole metabolites to inhibition of CYP3A4 in vivo
    I E Templeton
    Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington, USA
    Clin Pharmacol Ther 83:77-85. 2008
    ..Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone...
  38. ncbi Influence of CYP3A5 genotype on the pharmacokinetics and pharmacodynamics of the cytochrome P4503A probes alfentanil and midazolam
    E D Kharasch
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, St Louis, Missouri, USA
    Clin Pharmacol Ther 82:410-26. 2007
    ....
  39. ncbi Stereoselective analysis of bupropion and hydroxybupropion in human plasma and urine by LC/MS/MS
    Rebecka Coles
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, St Louis, MO 63110, USA
    J Chromatogr B Analyt Technol Biomed Life Sci 857:67-75. 2007
    ..The predominant enantiomers in both urine and plasma were (R)-bupropion and (R,R)-hydroxybupropion. This is the first LC-MS/MS assay to analyze the enantiomers of both bupropion and hydroxybupropion in plasma and urine...
  40. pmc The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity compared with the prototypical antagonist 2-methyl-6-(phenylethynyl)-pyridine
    Michael C Montana
    Washington University Pain Center, Department of Anesthesiology, 660 S Euclid Ave, St Louis, MO 63110, USA
    J Pharmacol Exp Ther 330:834-43. 2009
    ..These results demonstrate that fenobam is analgesic in mice and has an improved in vivo selectivity for mGlu5 over MPEP...
  41. pmc Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: II. Ritonavir effects on CYP3A and P-glycoprotein activities
    E D Kharasch
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, St Louis, Missouri, USA
    Clin Pharmacol Ther 84:506-12. 2008
    ..Ritonavir inhibited both intestinal and hepatic CYP3A and drug transport. ALF miosis noninvasively determined CYP3A inhibition by ritonavir...
  42. pmc Methadone metabolism and clearance are induced by nelfinavir despite inhibition of cytochrome P4503A (CYP3A) activity
    Evan D Kharasch
    Department of Anesthesiology, and Department of Biochemistry and Molecular Biophysics, Washington University in St Louis, St Louis, MO 63110, USA
    Drug Alcohol Depend 101:158-68. 2009
    ..CYP3A4/5 and transporters were assessed using alfentanil and fexofenadine, respectively...
  43. pmc Methadone pharmacokinetics are independent of cytochrome P4503A (CYP3A) activity and gastrointestinal drug transport: insights from methadone interactions with ritonavir/indinavir
    Evan D Kharasch
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St Louis, St Louis, Missouri 63110 1093, USA
    Anesthesiology 110:660-72. 2009
    ..CYP3A and transporters were assessed with alfentanil and fexofenadine, respectively...
  44. pmc Molecular characterization of CYP2B6 substrates
    Sean Ekins
    Collaborations in Chemistry, 601 Runnymede Ave, Jenkintown, PA 19046 USA
    Curr Drug Metab 9:363-73. 2008
    ..We have shown that CYP2B6 substrates are generally small hydrophobic molecules that are frequently central nervous system active, which may be important for drug discovery research...
  45. ncbi Role of CYP2B6 in stereoselective human methadone metabolism
    Rheem A Totah
    Department of Medicinal Chemistry, Washington University in St Louis, USA
    Anesthesiology 108:363-74. 2008
    ..Expressed CYP2B6 and also CYP2C19 N-demethylate methadone in vitro. This investigation tested the hypothesis that CYPs 2B6, 3A4, and/or 2C19 are responsible for stereoselective methadone metabolism in human liver microsomes and in vivo...
  46. doi Stereoselective bupropion hydroxylation as an in vivo phenotypic probe for cytochrome P4502B6 (CYP2B6) activity
    Evan D Kharasch
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, St Louis, MO 63110 1093, USA
    J Clin Pharmacol 48:464-74. 2008
    ....
  47. pmc Rapid clinical induction of hepatic cytochrome P4502B6 activity by ritonavir
    Evan D Kharasch
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, 660 S Euclid Ave, Campus Box 8054, St Louis, MO 63110 1093, USA
    Antimicrob Agents Chemother 52:1663-9. 2008
    ..The ritonavir induction of CYP2B6 activity may have significant implications for drug interactions and clarify previously unexplained interactions...
  48. pmc Stereoselective metabolism of bupropion by cytochrome P4502B6 (CYP2B6) and human liver microsomes
    Rebecka Coles
    Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, St Louis, Missouri 63110 1093, USA
    Pharm Res 25:1405-11. 2008
    ..Bupropion is chiral, used clinically as a racemate, and disposition is stereoselective. Nevertheless, it is unknown whether CYP2B6-catalyzed bupropion hydroxylation is stereoselective...
  49. ncbi Metabolism of alfentanil by cytochrome p4503a (cyp3a) enzymes
    Theresa Mariero Klees
    Department of Anesthesiology, Box 356540, University of Washington, 1959 NE Pacific, RR 442, Seattle, WA 98195, USA
    Drug Metab Dispos 33:303-11. 2005
    ..Alfentanil is one of the few CYP3A substrates that is metabolized in vitro as avidly by both CYP3A4 and 3A5. Polymorphic CYP3A5 expression may contribute to inter-individual variability in alfentanil metabolism...