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PHARMACOGENETICS & PHARMACOGENOMICS

PHARMACOGENETICS & PHARMACOGENOMICS. DRUGS CAN BE OBTAINED. Pharmacologists Study Science at Every Level. CAUSES OF FAILURE IN DRUG DEVELOPMENT. 10 % Adverse effects in man. Commercial reasons. 11% Animal toxicity. 39 % ADME. 30 % Lack of efficacy.

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PHARMACOGENETICS & PHARMACOGENOMICS

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  1. PHARMACOGENETICS & PHARMACOGENOMICS

  2. DRUGS CAN BE OBTAINED..

  3. Pharmacologists Study Science at Every Level

  4. CAUSES OF FAILURE IN DRUG DEVELOPMENT 10 % Adverse effects in man Commercial reasons 11% Animal toxicity 39 % ADME 30 % Lack of efficacy Kennedy, T, Drug Discovery Today, 1997

  5. Predictive ADME Absorption Distribution Metabolism Elimination Pharmacokinetic Metabolism BIOAVAILABILITY Hydrolysis Conjugation Oxidation, reduction

  6. DRUG METABOLISM PHASES Phase 1 Phase 2 % ionized at pH 7.4 0% 0.3% 99.9%+

  7. 25% 100% 25% Intestinal Lumen CYP 100% Pgp 50% 100% CYP 50% 50% 100% Role of Metabolism and P-glycoprotein Interaction and Its Influence on Absorption Liver Adapted from: Bailey, DG, et al. Br J Clin Pharmacol 1998:46:101-110

  8. Patients with the Same Diagnosis

  9. Pharmacologic Response to Therapy

  10. Responders Non-responders Toxic responders Genetically Based Optimization of Drug Dosing

  11. Non-responders Toxic responders Genetically Based Optimization of Drug Dosing

  12. PHARMACOGENOMICS PHARMACODYNAMICS PHARMACOKINETCS DRUG TARGETS, RECEPTORS METABOLIZING ENZYMES, TRANSPORTERS DRUG RESPONSE CHANGE

  13. PHARMACOGENETICS & PHARMACOGENOMICS Getting the right dose of right drug into the right patient

  14. “Every human differs “(more or less) Age Gender Ethnicity Diet Body composition Environment Illnesses Genetic make up

  15. SNPs • Single Nucleotide polymorphism • Most frequently observed genetic variation (1 Every 300-1000bp) • Variations can be rare or polymorphic (=common >1% in the population) • Can correlate with drug efficacy and toxicity

  16. MOLECULAR MECHANISMS OF GENETIC POLYMORPHISMS

  17. Synonymous, sense Nonsynonymous, missense

  18. Parent compound Less active drug metabolite More active drug metabolite Inactive drug metabolite Toxic drug metabolite

  19. Depending on the metabolic activity, four major cathegories of metabolizers are separated: extensive metabolizer (normal), intermediate metabolizer poor metabolizer, ultra-rapid metabolizer (increased metabolism of xenobiotics) 5-8% of Caucasians are phenotypically PM for CYP2D6

  20. Cytochrome P450 Metabolism The cytochromes involved in the metabolism are mainly monooxygenases that evolved from the steroid and fatty acid biosynthesis. So far, 17 families of CYPs with about 50 isoforms have been characterized in the human genome. classification: CYP 3 A 4 *15 A-B family>40% sequence-homology isoenzyme allel sub-family>55% sequence-homology

  21. Cytochrome P450 gene families

  22. Despite the low sequence identity between CYPs from different organisms, the tertiary structure is highy conserved.

  23. Cytochrome P450 Enzymes CYP 2D6 2% CYP 2A6 4% CYP 3 31% CYP 1A2 13% CYP 1A6 8% CYP 2C6 6% CYP 2C11 16% CYP 2E1 13%

  24. Substrate specificity of CYPs CYP 1A2 verapamil, imipramine, amitryptiline, caffeine (arylamine N-oxidation) CYP 2A6 nicotine CYP 2B6 cyclophosphamid CYP 2C9 diclofenac, naproxen, piroxicam, warfarin CYP 2C19 diazepam, omeprazole, propanolol CYP 2D6 amitryptiline, captopril, codeine, mianserin, chlorpromazine CYP 2E1 dapsone, ethanol, halothane, paracetamol CYP 3A4 alprazolam, cisapride, terfenadine, ...

  25. Cytochrome P450 Enzymes and drug metabolism Other 3% CYP 2C9 10% CYP 1A2 2% CYP 2D6 30% CYP 3A4 55%

  26. Alprenolol Amiodorone Apigenin Bufuralol Chloral hydrate Clonidine Clozapine Cyclobenzaprine Dexfenfluramine Dibucaine Dolasetron Encainide Ethylmorphine Flecainide Fluoxetine Guanoxan 4-hydroxy amphetamine Indoramine Laudanosine Loratadine Mefloquine Methoxyphenamine Methysergide HCl Metoprolol Moclobemide Mexiletine Nimodipine Nortriptyline Ondansetron Paroxetine Perphenazine Phenylpropanolamine Promethazine Propafenone pyrimethamine Rifampicin Roxithromycin Sparteine Tacrine Thioridazine Tomoxetine Tropisetron Amiflavine Amitryptiline Budesonide Bupranolol Clomipramine Clotrimazole Codeine Desipramine Dextromethorphan Dihydroergotamine Doxorubicin Ethinylestradiol Fenoterol Fluvoxamine maleate Formoterol Haloperidol Imipramine Keto(onazole Levomepromazine MDMA (ecstacy) Methoxamine HCI Methoxypsoralen Metoclopramide Minaprine MPTP Nicergoline Nitrendipine Olanzapine Oxprenolol Perhexiline Phenformin Procainamide N-propylajmaline Propranolol Quercitin Ritonavir Serotonin Sulfasalazine Tamoxifen Timolol Tranylcypromine Zuclopenthixol CYP2D6 drug substrates

  27. Dr. Robert Smith, Lancet Multiple copies Homozygous for the recessive alleles

  28. CYP 2D6 Polymorphism MGLEALVPLAVIVAIFLLLVDLMHRRQRWAARYPPGPLPLPGLGNLLHVDFQNTPYCFDQ LRRRFGDVFSLQLAWTPVVVLNGLAAVREALVTHGEDTADRPPVPITQILGFGPRSQGVF LARYGPAWREQRRFSVSTLRNLGLGKKSLEQWVTEEAACLCAAFANHSGRPFRPNGLLDK AVSNVIASLTCGRRFEYDDPRFLRLLDLAQEGLKEESGFLREVLNAVPVLLHIPALAGKV LRFQKAFLTQLDELLTEHRMTWDPAQPPRDLTEAFLAEMEKAKGNPESSFNDENLRIVVA DLFSAGMVTTSTTLAWGLLLMILHPDVQRRVQQEIDDVIGQVRRPEMGDQAHMPYTTAVI HEVQRFGDIVPLGMTHMTSRDIEVQGFRIPKGTTLITNLSSVLKDEAVWEKPFRFHPEHF LDAQGHFVKPEAFLPFSAGRRACLGEPLARMELFLFFTSLLQHFSFSVPTGQPRPSHHGV FAFLVSPSPYELCAVPR poor debrisoquine metabolism S R impaired mechanism of sparteine poor debrisoquine metabolism I poor debrisoquine metabolism R missing in CYP2D6*9 allele P loss of activity in CYP2D6*7 T impaired metabolism of sparteine in alleles 2, 10, 12, 14 and 17 of CYP2D6 see http://www.expasy.org/cgi-bin/niceprot.pl?P10635

  29. CONVERSION OF CODEINE TO MORPHINE CANNOT HAPPEN Poor metabolizers cannot activate codeine to morphine efficacy decrease for pain relief

  30. SSRIs: Excellent Money Makers.. US annual sales Phillips & Van Bebber 2005 Prozac: $1,577M Luvox: $126M Paxil (Seroxat): $2,468M

  31. CYP2D6 genotype based dose recommendations Kirchheineret al 2004

  32. Polymorphisms of further CYPs CYP 1A2 individual: fast, medium, and slow turnover of caffeine CYP 2B6 missing in 3-4 % of the caucasian population CYP 2C9 deficit in 1-3 % of the caucasian population CYP 2C19 individuals with inactive enzyme (3-6 % of the caucasian and 15-20 % of the asian population) CYP 2D6 poor metabolizers in 5-8 % of the european, 10 % of the caucasian, and <1% of the japanese population. Over expression (gene duplication) among parts of the african and oriental population. CYP 3A4 only few mutations

  33. CELLULAR TARGETS OF SN-38 IN THE BLOOD AND INTESTINAL TISSUES

  34. CYP2C19 POLYMORPHISM

  35. INTRONIC SNP EFFECTING SPLICING & ACCOUNT FOR POLYMORPHIC EXPRESSION OF CYP3A5

  36. P-Glycoprotein System • Product of multiple drug resistant-1 (MDR1) gene • In the family of ATP binding cassette (ABCs) • Cellular efflux transporter as a part of host defense but reducing intracellular accumulation • Variable expression of these transporters in sanctuary sites (CNS, genital tract), gut and lymphocytes • Associated with resistance to cancer chemotherapy • Known to have genetic polymorphisms that influence absorption and activity of “xenobiotics” • PGP also protects against viral infection, including HIV infection: • CD56+ cells with high PGP activity are resistant to infection by HIV

  37. PXR Intestinal Lumen Pgp Apical CYP Basolateral BLOOD VESSEL Pgp Plasma PI Concentration CD4+

  38. 100 OUT MEMBRANE IN P P P P Hypothetical Model of Human P-glycoprotein 200 ATP SITE ATP SITE 300 1200 A 1000 A B B 700 C C 400 800 900 1100 600 1 500 POINT MUTATIONS ( ), PHOTOAFFINITY LABELED 1280 REGIONS ( ), AND PHOSPHORYLATION SITES ( P )

  39. 1400 1000 Relative Pgp Levels 600 200 0 CC (n=3) CT (n=4) TT (n=1) MDR-1 C3435T Genotype and Digoxin Cmax C3435T (exon 26): • Lower P-glycoprotein levels • Higher blood digoxin levels Hoffmeyer et al (2000), PNAS 97, 3473-3478

  40. HAPLOTYPE BLOCKS

  41. Warfarin & Coumarin anticoagulating drugs In dosage adjustments of warfarin CYP2C9 and VKORC1 status should be checked

  42. Warfarin is used in the treatment of venous and arteria thromboembolic disturbances Warfarin is reduced with the help of Warfarin K epoxy reductase Significance of VKORC1 and CYP2C9 and MDR1 polymorphisms has been studied

  43. WARFARIN S-WARFARIN R-WARFARIN VKOR Vitamin K1 Epoxide (KO) Vitamin K1 (VK1) (ω-hydroxylation) Active F. II,VII,IX,X Proteins C,S,Z Hydroxyvitamin K1 GGCX (glutamylcarboxylase) Vitamin K1 Dihydroquinone (VKH2) Inactive F. II,VII,IX,X Proteins C,S,Z O2,CO2 49 WARFARIN METABOLISM Adapted from Gage et al. 2003

  44. WARFARIN DOSING & PHARMACOGENETICS

  45. Genotyping MaGNA Pure Compact Statistical Analysis Light Cycler 2.0

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