Lec 3

Question 1

What is the name of the molecule that allows drug molecules that are insoluble in blood to be carried?

Answer 1

human serum albumin (HSA)

Question 2

How many hydrophobic molecules in total can HSA carry?

Answer 2

7

Question 3

Describe how drug molecules carried by HSA can be deposited in the blood.

Answer 3

eqm can shift if there is a low concn of free molecules in the blood so that HSA releases these molecules

Question 4

Describe one method of visualising the localisation of drugs in the human body

Answer 4

positron emission tomography using 18F

Question 5

What are xenobiotic compounds and how are they metabolised in the body and marked for excretion?

Answer 5

• they are foreign compounds to the body
• marked in a 2 step process; oxidation and conjugation

Question 6

What is this reaction, name the enzyme that catalyses it and where this reaction takes place?

Answer 6

• hydroxylation reaction
• cytochrome P450 isozyme catalyses this hydroxylation reaction in the liver

Question 7

What other cofactor is commonly used in hydroxylation / oxidation reactions by P450 isozymes?

Answer 7

metal cofactor eg Fe

Fe’s transition states varies throughout this reaction

Question 8

When does a conjugation reaction occur?

Answer 8

after a molecule has been oxidised

Question 9

Give the name of a conjugate molecule and say what group acts as the nucleophile

Answer 9

glutathione

thiol group (R-SH) acts as the nucleophile

Question 10

Draw a VERY simple mechanism of the SH group of glutathione reacting with R - OH group

Answer 10

Question 11

Describe the 2 pathways that lead to the excretion of drug molecules

Answer 11

• KIDNEYS - blood is filtered via the kidneys and the glomeruli capillaries filter out drug molecules that are < 60 kDa and other substances eg water and glucose. Lpid drug molecules are reabsorbed (along with some glucose etc). those drugs that are not reabsorbed are excreted as urine
• ENTEROHEPATIC PATHWAY - any molecules that aren’t filtered can be taken up by the bile via active transport and pass into the intestine. further metabolism can occur & excretion can occur via stool. Or the drugs can be reabsorbed and re enter the blood

Question 12

What is the role the gut flora play in the excretion/not of drug molecules

Answer 12

sometimes the gut flora can cause the cleaveage of the conjugate molecule so that reabsorption occurs

Question 13

What can be done to increase the half life of a drug?

Answer 13

addition of various molecules to slow down its digestion

Question 14

Give 4 reasons as to why drugs (whilst being toxic) can have limited effectiveness

Answer 14

• too toxic so that it completely inactivates an enzyme for eg - rather than just downregulating the enzyme to normal levels
• too many targets witin the same family (eg multiple kinases)
• targets in different families - v hard to determine ALL targets of a drug. one target that all drugs are tested against is the K+ channel in the heart
• toxic metabolic byproducts

Question 15

Give an example of a toxic metabolic byproduct that is produced by a drug and how the body compensates to reduce its toxicity

Answer 15

• paracetamol hydroxyl group is turned into a carboxyl group during oxidation
• this carbonyl paracetamol is highly toxic to the liver
• liver glutathione molecules bind to the paracetamol and therefore reduces its toxicity
• however high doses of paracetamol leads to glutathione running out in the liver therefore other molecules (containing Cys groups) are used to bind to paracetamol
• this causes bad side effects