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1. Introduction
2. Overview
3. Adverse drug reactions
4. Mechanistic classification of drug reactions
5. Classification of adverse drug reactions
6. Products withdrawn from UK due to hepatotoxicity
7. Drug metabolism: pharmacology - background
8. Reminder: drug metabolism
9. Variation in drug metabolism - toxicity
10. Perhexilene maleate and CYP2D7
11. Lipidosis induced by amphiphilic cationic drugs
12. Prediction of variation in drug metabolism
13. Off target clinical adverse drug reactions
14. Drug metabolism: pharmacology - toxicity
15. Immune mediated hepatotoxicity and bioactivation
16. Metabolic basis of bioactivation and toxicity
17. Prediction of toxic metabolites - methods
18. Prediction of toxic metabolites - screens
19. Screens for metabolic reactivity
20. GSH conjugation
21. Nucleophile traps for electrophilic intermediates
22. Furosemide: hepatotoxicity (1)
23. Characterisation of a reactive FS intermediate
24. Trapping of FS intermediate by NAL and NAC
25. Furosemide: hepatotoxicity (2)
26. Screens for metabolic reactivity - covalent binding
27. Covalent binding to protein
28. How much covalent binding is acceptable: data
29. How much covalent binding is acceptable: results
30. Qualifying considerations
31. Prediction of toxic metabolites - design
32. 4-aminoquinoline antimalarials
33. Amodiaquine: metabolism and toxicity
34. 4-aminoquinolines: safety and efficacy in vitro
35. Isoquine: glucuronylation
36. Prediction of toxic metabolites - biology
37. Acetaminophen/paracetamol
38. Metabolism and toxicity of acetaminophen
39. Functional consequences of adduct formation
40. Mechanism of cell damage and critical proteins
41. Hepatocyte: defence against drug-induced stress
42. Mechanism of Nrf2-regulated gene induction
43. Hepatic nuclear translocation of Nrf2 (1)
44. Hepatic nuclear translocation of Nrf2 (2)
45. Acetaminophen hepatotoxicity in mice
46. Induction of Nrf2 by model hepatotoxins (1)
47. Induction of Nrf2 by model hepatotoxins (2)
48. Induction of Nrf2 by model hepatotoxins (3)
49. Nrf2 activation: NAPQI
50. Role of the adrenergic system
51. Drug metabolism: toxicology
52. Mechanism of cell damage: cell death (1)
53. Mechanism of HMGB1 in acetaminophen toxicity
54. Mechanism of cell damage: cell death (2)
55. HMGB1 compared with serum ALT levels
56. Effect of caspase inhibition: CK-18 and HMBG2
57. Chain of events from drug to toxicity
58. Making toxic or safe drugs
59. Conclusions

Topics Covered

• Classification of adverse drug reactions
• How this relates to the chemical structure of the offending drug
• Understanding how variation in drug metabolism can contribute to clinical toxicity is important in designing pre-clinical models and screens
• Case studies of drugs which can form reactive metabolites and can irreversibly modify cellular protein
• Examples of structural modifications to chemicals containing toxicophores
• Novel and traditional serum and cellular biomarkers of adaptation, apoptosis and necrosis

Links

Series:

• Non-Clinical Testing for Toxicity of Pharmaceuticals

Categories:

• Biochemistry
• Cell Biology
• Pharmaceutical Sciences

Talk Citation

Publication History

• Published on July 30, 2009
• Archived on June 15, 2016

Financial Disclosures

• Dr. Dominic Williams has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.