20091109 Biol1010 Personalized Medicine
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Personalized medicine involves the prescription of specific therapeutics best suited for an individual based on their genetic or proteomic profile. This talk discusses current approaches in drug discovery/development, the role of genetics in drug metabolism, and lawful/ethical issues surrounding the deployment of new health technology. I highlight some bioinformatic roles in the drug discovery process, and discuss the use of semantic web technologies for data integration and knowledge discovery..
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20091109 Biol1010 Personalized Medicine
- 1. Towards Personalized Medicine Michel Dumontier, Ph.D. Associate Professor of Bioinformatics Department of Biology, Institute of Biochemistry, School of Computer Science Carleton University Ottawa Institute for Systems Biology Ottawa-Carleton Institute for Biomedical Engineering Nov 9, 2009
- 16. CYP enzymes are involved in the metabolism of clinically important drugs S. Rendic Drug Metab Rev 34: 83-448, 2002 CYP Enzyme Examples of substrates 1A1 Caffeine , Testosterone , R-Warfarin 1A2 Acetaminophen , Caffeine , Phenacetin, R-Warfarin 2A6 17 -Estradiol, Testosterone 2B6 Cyclophosphamide, Erythromycin, Testosterone 2C-family Acetaminophen , Tolbutamide (2C9); Hexobarbital, S- Warfarin (2C9,19); Phenytoin, Testosterone , R- Warfarin , Zidovudine (2C8,9,19); 2E1 Acetaminophen , Caffeine , Chlorzoxazone, Halothane 2D6 Acetaminophen , Codeine, Debrisoquine 3A4 Acetaminophen , Caffeine , Carbamazepine, Codeine, Cortisol, Erythromycin, Cyclophosphamide, S- and R-Warfarin , Phenytoin, Testosterone , Halothane, Zidovudine
- 17. Factors Influencing Activity and Level of CYP Enzymes S. Rendic Drug Metab Rev 34: 83-448, 2002 Red indicates enzymes important in drug metabolism
- 18. Drug-Metabolizing Enzymes Pharmacogenomics: Translating Functional Genomics into Rational Therapeutics. Evans and Relling Science 1999 Most DME have clinically relevant polymorphisms Those with changes in drug effects are separated from pie. Phase I: modification of functional groups Phase II: conjugation with endogenous substitutents
- 19. Nortriptyline (anti-depressant) Pharmacogenetics Weinshilboum, R. N Engl J Med 2003;348:529-537
- 20. Weinshilboum, R. N Engl J Med 2003;348:529-537 Use of probe drugs to determine metabolic activity due to CYP2D6 variants Antihypertensive debrisoquin decreases blood pressure
- 29. Many factors contribute to drug recalls FDA: Center for Drug Evaluation and Research 2003 - Report to the Nation
- 30. VIOXX: Unknown Side Effects Treatment for Acute Pain increased risk of heart attack and stroke (after 18 months)
- 31. Diagnostics AmpliChip CYP450: Range of drug metabolism phenotypes is observed for individuals based upon the cytochrome P-450 genes
- 33. But wait a minute…
- 39. Personalied Medicine: What’s your take?
- 42. Drug Development Life Cycle Years 0 2 4 6 8 10 12 14 16 Discovery Preclinical Testing (Lab and Animal Testing) Phase I (20-30 Healthy Volunteers used to check for safety and dosage) Phase II (100-300 Patient Volunteers used to check for efficacy and side effects) Phase III (1000-5000 Patient Volunteers used to monitor reactions to long-term drug use) FDA Review & Approval Post-Marketing Testing
- 47. Most drugs approved are only slightly modified
- 48. Less innovative than you think
- 50. Profits as a Percentage of Assets, 2002 Top 7 of Fortune 500 Industries Source: Fortune Magazine, April 14, 2003
- 67. Microarrays Can Be Used To Determine Relative Gene Expression
- 71. combinatorial synthesis of non-peptide drugs + 1) 2) RXN 1 RXN 2
- 75. 3D QSAR for CYP3A4
- 76. 3D QSAR for CYP3A4 with known substrates
- 77. How to discover a drug
- 82. Structural bioinformatics to design nonpeptidic hydroxylates oral bioavailabity binding anti-growth anti-metastasis repeat…
- 87. How do we find this knowledge?
- 89. Surface web: 167 terabytes Deep web: 91,000 terabytes 545-to-one
- 90. How do we integrate these resources?
- 91. Data silos – not made for sharing
- 92. The Semantic Web will expose data and link knowledge
- 93. Bio2RDF is building the linked data web for biological data
- 94. Bio2RDF provides the methodology to create and glue these different databases.
- 96. Now Link Data! APP Protein is a Alzheimer’s Disease is a is involved in
- 97. something you can lookup or search for with rich descriptions
- 99. Semantic Knowledge Base APP Protein Is a Molecule is a is a fact ontology Knowledge base
- 101. Semantic Query Answering http://smart.dumontierlab.com ISWC Semantic Web Challenge: CS Honors: Alex De Leon
- 102. Build a knowledge base from a series of questions
- 103. Cell Simulation Molecules Interactions (metabolic/signaling) Compartments Cell Simulation + +
- 104. 3D Particle Simulation GridCell - Dr. Warren Gross & Laurier Boulianne, PhD Candidate Engineering
- 105. 3D Tetris or Science at Work?
- 106. Cellular Visions: The Inner Life of a Cell
- 107. Learn more and Get involved! BIOC 3008 [0.5 credit]: Bioinformatics BIOC 4008 [0.5 credit]: Metabolic Modeling and Simulation BIOC 2400 [0.5 credit]: Independent Research I BIOC 3400 [0.5 credit]: Independent Research II BIOC 4906 [1.0 credit]: Interdisciplinary Research BIOL 4900 [1.0 credit]: Biology Directed Special Studies BIOL 4901 [0.5 credit]: Biology Directed Special Studies BIOL 4908 [1.0 credit]: Biology Research Thesis BIOC 4907 [1.0 credit]: Biochemistry Essay and Research Proposal BIOC 4908 [1.0 credit]: Biochemistry Research Project CHEM 4908 [1.0 credit]: Chemistry Research Project and Seminar CMPS 4909 [1.0 credit]: Computational Science Research Thesis COMP 4901 [0.5 credit]: Computer Science Directed Studies COMP 4905 [0.5 credit]: Computer Science Research Thesis SYSC 4907 [0.5 credit]: Engineering Project
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- Excess amounts can lead to bone marrow toxicity, reducing the normal amounts of white and red blood cells
- 6-MP ribonucleotide inhibits purine nucleotide synthesis and metabolism. This alters the synthesis and function of RNA and DNA.
- congestive heart failure—the progressive weakening of the heart muscle to the point where it can no longer pump blood efficiently
- Most drug-metabolizing enzymes exhibit clinically relevant genetic polymorphisms . Essentially all of the major human enzymes responsible for modification of functional groups [classified as phase I reactions ( left )] or conjugation with endogenous substituents [classified as phase II reactions ( right )] exhibit common polymorphisms at the genomic level; Those enzyme polymorphisms that have already been associated with changes in drug effects are separated from the corresponding pie charts. The percentage of phase I and phase II metabolism of drugs that each enzyme contributes is estimated by the relative size of each section of the corresponding chart. ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; CYP, cytochrome P450; DPD, dihydropyrimidine dehydrogenase; NQO1, NADPH:quinone oxidoreductase or DT diaphorase; COMT, catechol O -methyltransferase; GST, glutathione S -transferase; HMT, histamine methyltransferase; NAT, N -acetyltransferase; STs, sulfotransferases; TPMT, thiopurine methyltransferase; UGTs, uridine 5'-triphosphate glucuronosyltransferases.
- Figure 4. Pharmacogenetics of Nortriptyline. Mean plasma concentrations of nortriptyline after a single 25-mg oral dose are shown in subjects with 0, 1, 2, 3, or 13 functional CYP2D6 genes. In addition, some subjects with ultrarapid metabolism have been shown to have multiple copies of the CYP2D6 gene. 18 Such subjects can have an inadequate therapeutic response to standard doses of the drugs metabolized by CYP2D6. Although the occurrence of multiple copies of the CYP2D6 gene is relatively infrequent among northern Europeans, in East African populations, the allele frequency can be as high as 29 percent. 22 The effect of the number of copies of the CYP2D6 gene — ranging from 0 to 13 — on the pharmacokinetics of the antidepressant drug nortriptyline is shown in Figure 4. 23 There could hardly be a more striking illustration of how genetics influences the metabolism of a drug.
- Approximately 5 to 10 percent of white subjects were found to have a relative deficiency in their ability to oxidize the antihypertensive drug debrisoquin. They also had an impaired ability to metabolize the antiarrhythmic and oxytocic drug sparteine. Subjects with poor metabolism of these two drugs had lower urinary concentrations of metabolites and higher plasma concentrations of the parent drug than did subjects with extensive metabolism A plot of the ratio of urinary debrisoquin to 4-hydroxydebrisoquin — a so-called metabolic ratio — is shown in Figure 3. The higher the metabolic ratio, the less metabolite was excreted. Therefore, subjects with poor metabolism are shown, counterintuitively, at the far right of the graph, with a few subjects at the far left of the frequency distribution who are now classified as having ultrarapid metabolism. As described subsequently, suchsubjects may have multiple copies of the gene for CYP2D6. Therefore, debrisoquin and sparteine represented “probe drugs” — compounds that could be used to classify subjects as having either poor metabolism or extensive metabolism. That strategy, the administration of a probe compound metabolized by a genetically polymorphic enzyme, became a standard technique used in many pharmacogenetic studies.
- Drug ﾐ drug interactions. The molecular basis of a drug - drug interaction. The orphan nuclear receptor PXR is a transcription factor that regulates the expression of the CYP3A gene (yellow) in the liver and intestine. It functions as a heterodimer with the nuclear receptor RXR. Drug A binds to PXR and induces expression of the CYP3A enzyme (pink), accelerating the metabolism of drug B, which is a substrate for CYP3A. CYP, cytochrome P450; OH, hydroxyl group; PXR, pregnane X receptor; RXR, retinoid X receptor.
- Figure 1. The Incidence-Rate Ratio for Sudden Death from Cardiac Causes According to the Current Use of the Study Antibiotic Medications and CYP3A Inhibitors. The bars indicate 95 percent confidence intervals. The reference group for the incidence-rate ratio associated with the concurrent use of erythromycin and CYP3A inhibitors and with the use of CYP3A inhibitors alone is the patients who used none of these medications; that for the incidence-rate ratio associated with the use of erythromycin and use of amoxicillin, regardless of the use of CYP3A inhibitors, is the patients who used neither of these antibiotic medications.
- Life-threatening opioid intoxication developed in a patient after he was given small doses of codeine for the treatment of a cough associated with bilateral pneumonia. Codeine is bioactivated by CYP2D6 into morphine, which then undergoes further glucuronidation. CYP2D6 genotyping showed that the patient had three or more functional alleles, a finding consistent with ultrarapid metabolism of codeine. We attribute the toxicity to this genotype, in combination with inhibition of CYP3A4 activity by other medications and a transient reduction in renal function. Figure 1. Metabolic Pathways of Codeine Biotransformation. The conversion of codeine into norcodeine by CYP3A4 and into codeine-6-glucuronide by glucuronidation usually represents 80 percent of codeine clearance, and conversion of codeine into morphine by CYP2D6 represents only 10 percent of codeine clearance (blue arrows). Morphine is further metabolized into morphine-6-glucuronide and into morphine-3-glucuronide. Morphine and morphine-6-glucuronide have opioid activity (green arrows). Glucuronides are eliminated by the kidney and are thus susceptible to accumulation in cases of acute renal failure. The patient (red arrows) had ultrarapid CYP2D6 metabolism, inhibition of CYP3A4 as a result of treatment with clarithromycin and voriconazole, and glucuronide accumulation due to acute renal failure. Red arrows with dotted lines indicate low levels of drug conversion or elimination, green arrows with dotted lines indicate low levels of brain penetration, and thick arrows indicate high levels.
- Research – that’s what brought you here Skils – marketable in whatever you choose to do thereafter Knowledeable – where the field has been and where it is going Improve oral and written scientific communication skills Research – tell people what you’ve been doing Track progress – develop a sense of progress
- Can’t answer questions that require background knowledge
- Transcription factor
- What inspires you?
- Reality: No formal training, peer networks? EDC training Human dynamic
- Reality: No formal training, peer networks? EDC training Human dynamic
- Thanks – CWV Hogue, Hogue Lab, Blueprint Team, Collaborators Funding – Carleton, NSERC, CFI, Health Canada Slides - Scott Brinker @ Chief Marketing Technologies