1. Drug Metabolism Overview Dr. Arthur Roberts 1

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

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 3

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

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

6. Functions: Toxin Removal bisphenol A Sulfonation Glucuronidation 6

7. Functions: Homeostasis and Regulation 7

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

9. What is the purpose of a prodrug? 9

10. Functions: Increased Toxicity Toxic Pathway 10

11. Pathways of Drug Metabolism Oxidation and Reduction Conjugation Drugs 11

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

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

14. Evans, W. E., and Relling, M. V. (1999) Pharmacogenomics: translating functional genomics into rational therapeutics, Science 286, 487-491. 14

15. Localization: Tissue Liver Intestines Kidneys 15

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 16

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

18. Regulation Induction Activation Inhibition 18

19. Regulation: Induction (Xie, 2004) 19

20. Regulation: Induction (Xie, 2004) DNA 20

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

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

23. Phase I “First Pass” Metabolism 23

24. Cytochrome P450 Hydroxylations Dealkylations 24

25. Non-cytochrome P450s Alcohol Dehydrogenase Epoxide Hydroxylase 25

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

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

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

29. Phase II Reactions 29

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

31. A B C D 31

32. Factors that Influence Drug Metabolism 32

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

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

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

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

37. Pregnancy (Choi, 2011 Biochemical Pharmacology) 37

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

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

40. Obesity Decreased MetabolismCYP3A4 Increased MetabolismUGTs, NAT, XO, CYP2E1, CYP1A2, CYP2C9, CYP2C19, CYP2D6 (Brill, 2012 Clinical Pharmacokinetics) 40

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

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

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

44. Ideas on how to deal with these differences? 44

45. End of Overview 45