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Talk: Clinical significance of enzyme induction and inhibi... (28 min)

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DETAILED SLIDE INDEX

  1. 1. Enzyme induc./inhibit. - significance
  2. 2. Cartoon
  3. 3. Variation in drug response
  4. 4. Basic pharmacology
  5. 5. Drug-drug interaction
  6. 6. Drug interactions - relevan./prevalen.
  7. 7. Perspective on drug interactions
  8. 8. Polypharmacy - clinical conseq.
  9. 9. Metabolic drug-drug interactions (1)
  10. 10. Metabolic drug-drug interactions (2)
  11. 11. Drug induc./inhibit. - examples
  12. 12. Drug interactions - examples
  13. 13. Drug-metabolising P450 isozymes
  14. 14. CYP1A2 activity - smoking/gender
  15. 15. Fluvoxamine-theophylline interaction
  16. 16. Fluvoxamine-clozapine interaction
  17. 17. Drug-metabolising P450 isozymes
  18. 18. Fluvoxamine-warfarin interaction
  19. 19. CYP2C19
  20. 20. Proguanil (antimalarial)
  21. 21. Single dose kinetics of proguanil
  22. 22. CYP2D6
  23. 23. Quinidine-imipramine interaction
  24. 24. Paroxetine-desipramine interaction
  25. 25. Fluoxetine-amitriptyline interaction
  26. 26. Hypothesis
  27. 27. M1 - O-demethylated tramadol
  28. 28. Tramadol pharmacokinetics - results
  29. 29. Paroxetine-tramadol interaction
  30. 30. Codeine metabolism in humans
  31. 31. Quinidine and codeine hypalgesia
  32. 32. Quinidine and codeine - pharmacok.
  33. 33. Quinidine and codeine - side effects
  34. 34. Adverse drug reactions
  35. 35. Hypothesis
  36. 36. CYP3A4
  37. 37. Quinidine-rifampicin interaction
  38. 38. Repaglinide-rifampicin interaction
  39. 39. Nortriptyline-carbamazepine interac.
  40. 40. Enzyme induc./inhibit. - significance

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TALK'S CITATION

Brosen, K. (2007), "Clinical significance of enzyme induction and inhibition", in Daly, A. (ed.), Drug Metabolizing Enzymes: Fundamentals, Study Methods, Recent Advances and Clinical Significance, The Biomedical & Life Sciences Collection, Henry Stewart Talks Ltd, London (online at http://hstalks.com/?t=BL0091099)

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ABOUT THIS TALK

Speaker(s)

Prof. Kim Brosen Show Biography

SPEAKER BIOGRAPHY

Prof. Kim Brosen – Institute of Public Health, Clinical Pharmacology, University of Southern Denmark

Kim Brosen was born in Copenhagen, Denmark, in 1954. In 1995 he was appointed Professor in Human Pharmacology at the University of Southern Denmark in Odense. Prof. Brosen became Consultant in Clinical Pharmacology at the Department KKA, Odense University Hospital in 1991. He was appointed Editor of "Basic & Clinical Pharmacology & Toxicology in 2003. He is Honorary President of the European Association for Clinical Pharmacology and Therapeutics (EACPT). Prof. Brosen has published approximately 200 papers including approximately 140 original papers in international journals with peer review, and was among the most cited pharmacologists during 1990 to 2004.

Publication Date

October, 2007

Topics Covered

Metabolic drug interactions... more

TOPICS COVERED IN THIS TALK

  • Metabolic drug interactions
  • Prediction of significant drug interactions
  • Identifying clinically important mechanisms
  • Therapeutic index
  • Clinical dose titration

Series

Drug Metabolizing Enzymes

OTHER TALKS IN THIS SERIES

INTRODUCTION
Play '1. Editor's Foreword'
1. Editor's Foreword More info
Prof. Ann Daly

TOPICS COVERED IN THIS TALK

  • Genes and gene products
  • Role of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 in drug metabolism
  • Regulation of gene expression
  • Effect of genetic variation
  • Clinically relevant polymorphisms
Play '2. Introduction to drug metabolism enzymes'
2. Introduction to drug metabolism enzymes More info
Dr. Dennis Smith

TOPICS COVERED IN THIS TALK

  • Metabolism of lipophilic molecules
  • Phase I and Phase II enzymes
  • Location
  • Mechanism
  • Typical substrates
  • Genetic variation
  • Species variation
  • Inhibition and drug interactions
  • Drug design
GENERAL FACTORS AFFECTING DRUG METABOLISM
Play '3. General factors affecting drug metabolism: the role of nuclear receptor superfamily members in induction'
3. General factors affecting drug metabolism: the role of nuclear receptor superfamily members in induction More info
Dr. Patrick Maurel

TOPICS COVERED IN THIS TALK

  • Drug metabolism and gene transcription
  • Role of nuclear receptors in drug metabolism induction
  • Aryl hydrocarbon receptor
  • Pregnane X receptor
  • Constitutive androstane receptor
  • Human examples of drug metabolism induction
Play '4. Effect of physiological factors and disease on drug metabolism'
4. Effect of physiological factors and disease on drug metabolism More info
Prof. Edward Morgan

TOPICS COVERED IN THIS TALK

  • Effect of physiological and pathophysiological conditions on drug metabolizing enzymes (DMEs)
  • Role of growth hormones and transcription factors in sex-dependent expression
  • Drug clearance and age
  • Developmental regulation
  • Impact of infection and inflammatory disease on DME expression
  • Clinical consequences
Play '5. Drug metabolism and liver disease'
5. Drug metabolism and liver disease More info
Prof. Robert Branch

TOPICS COVERED IN THIS TALK

  • Liver disease and drug clearance
  • Mechanistic explanations
  • Intact hepatocyte hypothesis
  • Sick cell theory
  • Sequential progressive model of liver disease
  • Viral liver disease
  • Alcoholic liver disease
  • Hepatocellular carcinoma
  • Liver transplantation
Play '6. Laboratory methods for the in vitro study of drug metabolism'
6. Laboratory methods for the in vitro study of drug metabolism More info
Dr. Charles Crespi

TOPICS COVERED IN THIS TALK

  • Major classes of DMEs
  • Systems for laboratory study
  • Practical aspects
  • Examples of application
  • Obtaining high quality data
  • Minimizing artefacts
Play '7. Prediction of pathways of drug metabolism'
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Dr. Maurice Dickins

TOPICS COVERED IN THIS TALK

  • Methods of in silico prediction based on substrates and DMEs
  • Computer based approaches
  • Predicting sites of metabolism
  • Predicting metabolic pathways
  • Mass spectroscopy for identifying metabolites
PHASE I METABOLIZING ENZYMES: CYTOCHROME P450S
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8. Crystal structures of drug-metabolizing P450 monooxygenases More info
Prof. Eric Johnson

TOPICS COVERED IN THIS TALK

  • Introduction to CYP450 architecture
  • Shared structural features
  • Catalytic mechanism
  • Redox partner interactions
  • Membrane topology
  • Multiple modes of substrate binding and oxidation
Play '9. Catalytic cycle of cytochrome P450s'
9. Catalytic cycle of cytochrome P450s More info
Prof. Gordon Roberts

TOPICS COVERED IN THIS TALK

  • Catalytic cycle of cytochrome P450s
  • Substrate and oxygen binding
  • Key electron and proton transfers
  • Dioxygen cleavage
  • Formation of the 'activated oxygen' hydroxylating species
  • Structure and electron transfer properties of NADPH-cytochrome P450 reductase
  • Possible roles of cytochrome b5 in the p450 monooxygenase system
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10. Cytochrome P450 1 Family: the roles of 1A1, 1A2 and 1B1 in drug metabolism More info
Prof. F. Peter Guengerich

TOPICS COVERED IN THIS TALK

  • Family 1 P450s
  • Substrates
  • Regulation
  • Polymorphisms
  • Levels of activity and cancer
  • Adverse drug reactions
  • P450 systems and drug development
  • Molecular epidemiology in cancer issues
Play '11. CYP2 family'
11. CYP2 family More info
Prof. Ann Daly

TOPICS COVERED IN THIS TALK

  • Genes and gene products
  • Role of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 in drug metabolism
  • Regulation of gene expression
  • Effect of genetic variation
  • Clinically relevant polymorphisms
Play '12. Why Study the Cytochrome P4503A (CYP3A) Family?'
12. Why Study the Cytochrome P4503A (CYP3A) Family? More info
Dr. Erin Schuetz

TOPICS COVERED IN THIS TALK

  • Role of CYP3A4, CYP3A5 and CYP3A7 in drug metabolism
  • Gene expression
  • Molecular mechanisms of regulation
  • Enzyme induction and inhibition
  • Polymorphic variation
  • Inter-individual variation
  • Drug-drug interactions
Play '13. Pharmacogenetics of the P450s'
13. Pharmacogenetics of the P450s More info
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TOPICS COVERED IN THIS TALK

  • Effect on metabolism of polymorphic enzymes
  • Duplication, multiduplication or amplification of active P450 genes
  • Reduced drug efficacy and adverse reactions
  • Drug dose
  • Polymorphisms and cancer risk
  • Evolutionary basis and interethnic differences
  • Genetic drift vs. positive selection
  • Pharmacogenetic diagnostics
PHASE I METABOLIZING ENZYMES: NON-CYTOCHROME P450S
Play '14. Non-P450 oxidative metabolism: characteristics and drug substrates'
14. Non-P450 oxidative metabolism: characteristics and drug substrates More info
Dr. Christine Beedham

TOPICS COVERED IN THIS TALK

  • Cytosolic, mitochondrial and microsomal enzymes in drug oxidation
  • Molybdoflavoproteins
  • Aldehyde oxidase
  • Xanthine oxidase
  • NAD(P)-dependent aldehyde dehydrogenase
  • NAD+-dependent alcohol dehydrogenase
  • Monoamine oxidase
  • Flavin Monooxygenase
  • Co-oxidation by prostaglandin synthase and lipoxygenases
  • Role in drug activation and inactivation
  • Factors affecting activity
Play '15. Genetic Variability in Paraoxonase 1 (PON1), an HDL associated Esterase: Impact on Risk and Pharmacokinetics'
15. Genetic Variability in Paraoxonase 1 (PON1), an HDL associated Esterase: Impact on Risk and Pharmacokinetics More info
Res. Prof. Clement Furlong

TOPICS COVERED IN THIS TALK

  • Paraoxonase (PON1)
  • Hydrolytic reactions
  • Enzyme properties
  • Polymorphisms
  • Use of mouse models
  • PON1 levels in human populations
  • PON1 status as a risk factor in carotid artery disease
  • Designing epidemiological studies for examining PON1 genetic variability and risk
PHASE II METABOLIZING ENZYMES: CONJUGATING ENZYMES
Play '16. Glucuronidation and the UDP - glucuronosyltransferases'
16. Glucuronidation and the UDP - glucuronosyltransferases More info
Prof. Peter Mackenzie
Prof. John Miners

TOPICS COVERED IN THIS TALK

  • The glucuronidation reaction
  • UGT enzyme superfamily
  • Importance for xenobiotic and drug metabolism
  • Substrate and inhibitor specificities
  • Gene regulation
  • Tissue specific expression
  • Genetic polymorphism
  • Structure/function relationships
  • Kinetic considerations
Play '17. Sulfation and human cytosolic sulfotransferases'
17. Sulfation and human cytosolic sulfotransferases More info
Prof. Charles Falany

TOPICS COVERED IN THIS TALK

  • Cytosolic sulfotransferase (SULTs) gene family
  • Physiological and pharmacological activity
  • Xenobiotic and drug conjugation
  • Substrate specificities
  • Major groups SULT1 and SULT2
  • Tissue-specific expression and regulation
Play '18. Glutathione transferases'
18. Glutathione transferases More info
Prof. Ralf Morgenstern

TOPICS COVERED IN THIS TALK

  • Isoform properties
  • Functional significance
  • Protection from toxicity and genotoxicity
  • Gene knock-out models
  • Oxidative stress and cytostatic drugs
  • Pharmacogenetics
  • Biochemical transformations in catabolism
  • Signalling events
  • Biosynthesis of endogenous lipid mediators
  • Prostaglandin and leukotriene pathways
Play '19. Arylamine N-acetyltransferases'
19. Arylamine N-acetyltransferases More info
Prof. Edith Sim

TOPICS COVERED IN THIS TALK

  • Mechanism of action
  • Reaction substrates
  • Isoform substrate profiles
  • Isoenzymes NAT1 and NAT2
  • Regulation of gene expression
  • Pharmacogenetics
  • Phenotype/genotype correlation
  • Ethnic variation
  • Transgenic mouse models
Play '20. Methyltransferases'
20. Methyltransferases More info
Prof. Richard Weinshilboum

TOPICS COVERED IN THIS TALK

  • Properties, structure, catalytic cycle, isoforms and drug substrate specificity of the main methyltransferase families contributing to drug metabolism
  • Regulation of gene expression
  • Pharmacogenetics
Play '21. Amino acid conjugation: contribution to the metabolism and toxicity of xenobiotic carboxylic acids'
21. Amino acid conjugation: contribution to the metabolism and toxicity of xenobiotic carboxylic acids More info
Dr. Kathleen Knights

TOPICS COVERED IN THIS TALK

  • Conjugation reaction pathway
  • Forms of CoA ligase
  • Activity of mitochondrial N-acyltransferases
  • Substrates for amino acid conjugation
  • Effect of limited CoASH on cellular processes
  • Mitochondrial toxicity
  • Implications for rational drug design
CLINICAL ASPECTS
Now Playing
22. Clinical significance of enzyme induction and inhibition
Prof. Kim Brosen
Play '23. Clinical importance of pharmacogenetic polymorphisms affecting drug metabolism: psychopharmacology and pain'
23. Clinical importance of pharmacogenetic polymorphisms affecting drug metabolism: psychopharmacology and pain More info
Prof. Julia Stingl (formerly Kirchheiner)

TOPICS COVERED IN THIS TALK

  • Pharmacogenetic polymorphisms
  • Biotransformation and clinical outcome
  • Consequences of genotyping
  • Feasibility for genotyping in antidepressant drug treatment
  • Polymorphic cytochrome P450 enzyme CYP2D6
  • Feasibility for genotyping in pain treatment
  • CYP2C9, CYP2D6 and nonsteroidal analgetic drugs
Play '24. Clinical importance of pharmacogenetic polymorphisms affecting drug metabolism: internal medicine'
24. Clinical importance of pharmacogenetic polymorphisms affecting drug metabolism: internal medicine More info
Prof. Julia Stingl (formerly Kirchheiner)

TOPICS COVERED IN THIS TALK

  • Cardiovascular drugs and genetic polymorphisms
  • Antihypertensive drug treatment
  • Feasibility for genotyping
  • Cancer treatment and genetic polymorphisms
  • Potential for pharmacogenetic diagnostics
  • Thiopurine-methyl-transferase (TPMT)
  • Dihydropyrimidine dehydrogenase
  • Efficacy of antiemetic treatment
  • Future clinical study directions in pharmacogenetics
LATEST UPDATES IN THE FIELD
Play '25. Mammalian flavin-containing monooxygenases'
25. Mammalian flavin-containing monooxygenases More info
Prof. Allan Rettie

TOPICS COVERED IN THIS TALK

  • Flavin-containing monooxygenases (FMOs)
  • FMO structure, function and regulation
  • Role of FMOs drug metabolism and drug toxicity
  • Methods for distinguishing between FMO and P450 catalysis

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