Drug metabolism tutorial

Question 1

What is paracetemol converted to by phase 1

Answer 1

NAPQI

Question 2

Normal dose of paracetemol and how many times it can be taken and thus max daily dose

Answer 2

1g every six hours- max 4 grams per day

Overdose is 10-15grams so small therapeutic!

Question 3

What is the problem with drinking and paracetemol

Answer 3

Ethanol inhibits the cytochrome p450 so paracetemol broken down less well.

Question 4

What is the dangerous molecule in paracetemol

Answer 4

NAPQI because it is an electrophile- it reacts with glutathione. The biggest problem is not attacking the DNA but of the proteins in the hepatocyte so hepatocellular damage

Question 5

What phase 2 reactions used with paracetemol?

Answer 5

glutathione conjugation, sulfation or glucuronidation (by glucuronile transferase) and tiny bit of methylation

Question 6

What does the sulfate react with when conjugating

Answer 6

Hydroxyl groups- so the hydroxyl group at the bottom of the paracetemol using sulphate transferase enzyme

Question 7

Which co-enzyme is used in glucuronidation

Answer 7

UDPGA

Question 8

Where is the sugar added in the glucuronidation reaction?

Answer 8

Hydroxyl group

Question 9

Which 2 carbons are electrophilic in the NAPQI

Answer 9

To either side of the oxygen double bond so this is the site of glutathione conjugation (by glutathione transferase)

Question 10

What would you do with a paracetemol overdose patient

Answer 10

1) Stomach pump

2) Give methionine

Question 11

Where would the paracetemol be after 12 hrs

Answer 11

In the blood and thus the liver

Question 12

Why can glutathione not be given so what do you give instead

Answer 12

It cannot cross biological membranes so cannot get out of the blood into the cell membranes of the liver. Cysteine can be given but we give oral methionine instead (acts in the same way) or i.v n-acetyl cysteine. If it’s within 24 hrs it might be okay, but after that they’ll become unconscious, coma, kidney damage etc.

Question 13

Problem with the NAPQI relating to the kidney

Answer 13

Damages the kidney such that the NAPQI can then not be excreted

Question 14

Which metabolite of paracetemol would be found in the bile

Answer 14

Glutathione conjugate, and glucuronide conjugate (some of it)- because these are high molecular weight conjugates (heavy)

Question 15

Which metabolite of paracetemol would be found in the urine

Answer 15

Sulfate conugates, glucuronide conjugates (some of it) and mercapturic acid derivates (comes as a product of conjugating compounds with cysteine)

Question 16

Which metabolite of paracetemol would be found in the blood

Answer 16

Paracetemol itself (not 100% first pass metabolism so some will be passing through the liver unmetabolised first time) and all of the metabolites going to the kidney for excretion

Question 17

Why is plasma half life longer in overdosed patient

Answer 17

Glucuronidation enzymes are at saturation, damage to liver due to the NAPQI so impaired ability to conjugate etc, and damage to the kidneys, and depletion of sulfate

Question 18

What is acetanilide

Answer 18

Prodrug of paracetemol. Oxidised by cytochrome p450 to make paracetemol (by addition of hydroxyl group- so it’s just paracetemol without a hydroxyl group)

Question 19

Why isn’t acetanilide used

Answer 19

Causes methaemoglobinaemia

Question 20

First reaction to the left of parent compound

Answer 20

Hydroxylation by cytochrome p450

Question 21

Reaction between parent compound and the reaction below it

Answer 21

Reduction of nitrate to the amine, by a reductase (mostly gut bacteria)

Question 22

What happens from the one directly below the parent molecule, to the one after that

Answer 22

acetyl group added, by an N-acetyl transferase + acetyl CoA

Question 23

What happens from parent compound to the one to the right

Answer 23

ester to carboxylic acid, so it’s a hydrolysis reaction by enzyme called esterase

Question 24

What happens from molecule to the right of the parent molecule to the one below it

Answer 24

Glucuronidation by glucornile transferase, UDPGA

Question 25

What happens from molecule to the right of the parent to get to the molecule further right

Answer 25

Carboxylic acid to the amide, so a carboxylic acid has been added (by glycine), by acyl CoA ligase and glycine (cofactor)

Question 26

Which metabolite would you NOT get if the drug was administered via a patch

Answer 26

The reductase mediated reaction (because it doesn’t pass through the gut), but if it was taken orally then it would need form the reductase