Question 1. (1 pg) The following two structures are provided
a) Examine structures A and B. Briefly identify in writing and describe parts of the molecule (as structural moieties drawn in your answer) of A and (separately) B that are initially metabolized. Provide (draw) the chemical structure of the anticipated initial metabolite(s). If there are few metabolites, so state and indicate why (with a chemical or biochemical explanation). b) Predict the approximate half-life values after separate oral administration of A or B. What structural or metabolic feature(s) helps determine the half-life?
Question 2. (½ pg) Draw 2-acetylaminofluorene.
a) Describe at least 6 metabolites that could arise from metabolism of 2-acetylaminofluorene. b) For 3 of the metabolites, briefly describe the enzyme(s) responsible for metabolite formation. c) For the 3 enzymes systems described as selected above, indicate whether the enzyme is inducible or prone to genetic polymorphisms and whether these mechanisms play a role in formation of the metabolite. Question 3. (½ pg) Consider that you are a drug metabolism scientist charged with defining the experimental approach to human drug metabolism of a new chemical entity (NCE).
a) Describe the 1st study you would do with the NCE and explain why you would do it. b) What is the concentration of the NCE used in these studies and why? c) What is the 2nd metabolism experiment you would do and why would you do this study? d) When would you do specific studies with inhibitors or induction studies and why?
Question 4. (1 pg) Briefly, (300 words or less) describe your understanding of the conversion of a specific drug or xenobiotic (your choice) to a specific electrophilic species or metabolite that could result in toxicity to humans.
a) Provide a detailed example by illustrating with chemical structures/metabolites. b) Present any evidence (including describing metabolite structures and enzymes) and discuss the role of metabolic processes (oxidation, conjugation, etc.) in the generation of the reactive material and/or the detoxication of the metabolite chosen above.