CHY8822 - Drug Metabolism and Toxicology Assignment

Assignment Task

Section

A. Pharmacokinetics and Metabolism

(a) Draw idealized plots of plasma concentration versus time for a drug dosed intravenously and orally.

(b) Define the parameters of clearance, volume of distribution and bioavailability and describe how they are defined from the plots you have drawn.

(c) Suggest likely products arising from cytochrome P450 (CYP) mediated oxidation of the compounds containing benzene rings such as 1, benzylic methyl groups as in 2 and alkenes such as in 3.

(d) Give mechanisms for each of these transformations.

After being dosed orally to a rat, no blood levels of compound 4 were detected.

(a) Describe the reasons why this might be the case.

(b) Identify which of these reasons are most likely (you can choose more than one)

(c) For each reason you gave, suggest a further experiment or test that could be done to help decide whether that was the cause of the problem.

(d) Can you suggest two structural modifications of compound 4 that would address the problems you have highlighted giving reasons for your decisions?

B. Toxicology

(a) Define the terms acute and chronic toxicity and explain the differences between the two.

(b) Define the terms LD50 and ED50. Explain how these terms are used to define the therapeutic index and what it means.

(c) Draw a dose-response curve for a compound with an LD50 of 50 mg/kg and a therapeutic index of 5.

Describe the structural and physicochemical features of drug molecules that give rise to hERG binding. With reference to your answer, describe why loperamide 8 is a channel blocker. Suggest two changes to the structure that might reduce its hERG activity, giving reasons for your choices. Suggest two reasons why compound 9 might be toxic. For each one, suggest a modification to the structure that might reduce the toxicity.

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