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Drug Metabolism Overview

Drug Metabolism Overview. Dr. Arthur Roberts. Where to Find Information. eLC www.pharmwiki.org most up to date correct errors. Outline. Introduction ADME Functions Phase I versus Phase II Metabolism Enzymes Localization Regulation Phase I Metabolism Types of Reactions

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Drug Metabolism Overview

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  1. Drug Metabolism Overview Dr. Arthur Roberts

  2. Where to Find Information • eLC • www.pharmwiki.org • most up to date • correct errors

  3. Outline • Introduction • ADME • Functions • Phase I versus Phase II Metabolism • Enzymes • Localization • Regulation • Phase I Metabolism • Types of Reactions • First Pass Effect • Phase II Drug Metabolism • Types of Reactions • Factors that Influence Drug Metabolism • Considerations and Methods

  4. Metabolites Drug Metabolism Absorption Blood Non-enzymatic Drug Excretion Distribution

  5. Functions • Good • Drug Clearance • Toxin Removal* • Homeostasis and Regulation* • Prodrug (inactive)  Active Drug* • Bad • Reduced Efficacy • Increased Toxicity*

  6. Functions: Toxin Removal bisphenol A Glucuronidation Sulfonation

  7. Functions: Homeostasis and Regulation

  8. Functions: Prodrug Drug Antidepressant Antihistamine Antihistamine Analgesic (Fura et al., 2004)

  9. What is the purpose of a prodrug?

  10. Functions: Increased Toxicity Toxic Pathway

  11. Pathways of Drug Metabolism Drugs Oxidation and Reduction Conjugation

  12. Phase I versus Phase II? A B C D

  13. Why is it called Phase I and Phase II drug metabolism?

  14. Evans, W. E., and Relling, M. V. (1999) Pharmacogenomics: translating functional genomics into rational therapeutics, Science286, 487-491.

  15. Localization: Tissue Liver Intestines Kidneys

  16. Localization: Subcellular • Phase I • Cytochrome P450s (P450s or CYPs)-ER lumen • Flavin-Containing Monooxygenase (FMO)-ER lumen • Alcohol Dehydrogenase (ADH)-Cytosol • Phase II • UDP-glucuronosyltransferases (UGTs)- ER lumen • Membrane-bound Sulfotransferases (SULTs)- Golgi Apparatus • Cytosolic Glutathione-S-Transferases (GSTs)- Cytosol

  17. What is the purpose of a drug-metabolizing enzyme being membrane bound?

  18. Regulation • Induction • Activation • Inhibition

  19. Regulation: Induction (Xie, 2004)

  20. Regulation: Induction DNA (Xie, 2004)

  21. Regulation: Activation Rate of Metabolite formation Testosterone Drug Concentration

  22. Regulation: Inhibition Bergamottin Rate of Metabolite Formation Inhibitor Concentration

  23. Phase I “First Pass” Metabolism

  24. Cytochrome P450 Hydroxylations Dealkylations

  25. Non-cytochrome P450s Alcohol Dehydrogenase Epoxide Hydroxylase

  26. First Pass Effect • concentration of a drug is greatly reduced before it reaches the systemic circulation. Lidocaine Morphine Demerol (opioid analgesic) (synthetic opioid analgesic) (local anesthetic)

  27. First Pass Effect Which corresponds to first pass effect? IV Concentration in Blood Oral Time

  28. Systems Involved Liver Gastrointestinal Stomach (Gut Wall) Bacteria

  29. Phase II Reactions

  30. Phase II Enzymes Glutathione-S-transferases (GSTs) N-acetyltransferases (NATs) UDP Glucuronosyltransferases (UGTs)

  31. A B C D

  32. Factors that Influence Drug Metabolism

  33. Genetics Differences in Hydrocodone metabolite formation in Cytochrome P450 2D6 Extensive Metabolizer Poor Metabolizer (Reynolds, 2008 Clinics in Laboratory Medicine)

  34. Ethnic Groups web2.uconn.edu/rusling/Carl_Davis1.ppt

  35. Aging (Kinirons, 2003, British Journal of Clinical Pharmacology)

  36. Gender Male Normalized mRNA Expression Level Female [Drug] Circles=Nicardipine Triangles=Nifedipine (Konno, 2004 Toxicology and Applied Pharmacology)

  37. Pregnancy (Choi, 2011 Biochemical Pharmacology)

  38. Food, Diet and Nutrition (Kola nut, grape, green tea and Ginkgo biloba) (Ryu, 2003 Food and Chemical Toxicology)

  39. Food, Diet and Nutrition chronic grapefruit juice Felodipine (Calcium Channel Blocker) acute grapefruit juice water (Lown, 1997 Journal of Clinical Investigation)

  40. Obesity (Brill, 2012 Clinical Pharmacokinetics)

  41. Habits: Alcoholism A- Non-alcoholic B- Chronic alcohol consumption A B (Lieber, 2008 Biochemical and Biophysical Research Communication)

  42. Habits: Smoking (Ryu, 2003 Food and Chemical Toxicology)

  43. Factors that Influence Drug Metabolism • Genetics • Ethnic Groups • Age • Gender • Pregnancy • Food, Diet and Nutrition • Obesity • Habits (Smoking/Alcohol)

  44. Ideas on how to deal with these differences?

  45. End of Overview

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