ADME part 2

Question 1

What typically results from metabolism of a drug?

Answer 1

A more polar metabolite which is often inactive and/or less likely to diffuse through cells and reach receptors and more likely to be excreted in the urine or bile

Question 2

What are the unusual results of drug metabolism?

Answer 2

In the case of prodrugs there can be promotion of activity by metabolism
A few drugs will have metabolism not change their activity (such as diazepam to nordiazepam)
Some drugs such as paracetamol can produce toxic metabolism

Question 3

What are examples of prodrugs?

Answer 3

Codeine to morphine

Acetylsalicylate to salicylate

Question 4

What are the phases of drug metabolism?

Answer 4

Phase one reactions which uncover or add a reactive group making the molecule more susceptible to phase 2 reactions
Phase two reactions which involve conjugation of an endogenous molecule with a drug
Phase one reactions are not always required

Question 5

What type of chemical reactions make up phase one drug metabolism interactions?

Answer 5

Oxidation, reduction and hydrolysis

Question 6

What type of chemical reactions make up phase two drug metabolism reactions?

Answer 6

Conjugation with glucuronide, sulphate, amino acids or glutathione as well as acetylation of the drug

Question 7

What is the most important type of phase one drug reactions?

Answer 7

Oxidation, which is typically performed by the cytochrome p450 dependent mixed function oxidases

Question 8

What are the cytochrome P450 dependent mixed function enzymes?

Answer 8

A family of closely related oxidative enzymes that are located on the smooth endoplasmic recticulum
CYP1,2 and 3 encode most of the enzymes involved in drug metabolism

Question 9

How does the microsomal cytochrome p450 monooxygenase reaction occur?

Answer 9

The drug combines with CYP in the oxidised state
The complex is then reduced by a reductase transferring an electron from NADPH
A second electron from the same source serves to reduce oxygen to from an activated oxygen-CYP complex
Complex splits into the oxidised drug, water and the oxidised CYP

Question 10

What is the overall chemical reaction of drug oxidation by Cytochrome P450?

Answer 10

Drug + O2 + NADPH to Oxidised drug + H2O + NADP+

Question 11

How are CYPS named?

Answer 11

CY(tochrome)P(450) Number of Family-Letter of subfamily-isoform

Question 12

What does CYP 1A1/2 metabolise?

Answer 12

Procarcinogens, promutagens, caffeine and theophylline

Question 13

What does CYP 2C9 metabolise?

Answer 13

R-Mephenytoin, S-Warfarin, omeprazole

Question 14

What does CYP 2D6 metabolise?

Answer 14

Debrisoquine, spareine, codeine, various beta-blockers and tricyclic antidepressants

Question 15

What does CYP3A4 metabolise?

Answer 15

Cyclosporine, nifedipine, erythromycin, terfenadine, theophylline, tesosterone

Question 16

What induces CYP1A1/2?

Answer 16

Benzo(a)pyrenes in cigarette smoke and BBQ meat

Question 17

What inhibits CYP2D6 metabolism?

Answer 17

Quinidine, fluphenazine and fluoxetine

Question 18

What inhibits CYP3A4 metabolism?

Answer 18

Quinolones, ketoconazole, erthyromycin and grapefruit juice)

Question 19

What induces CYP3A4 metabolism?

Answer 19

rifampicin, glucocorticoids and barbiturates

Question 20

What is the process of induction of CYP enzymes?

Answer 20

There is enzyme synthesis initiated within 24 hours of exposure, increasing over 3-5 days
The effect of this decreases over 1-3 weeks after inducing agent is discontinued

Question 21

What is the time scale of inhibition of CYP enzymes?

Answer 21

An effect where there is a rapid onset within one day and an exaggerated response to drug with an increased risk of toxicity is observed

Question 22

What are the compounds that can result in CYP inhibition?

Answer 22

Competitive reversible inhibitors such as cimetidine, ketoconazole, quinolone, oestrogens and grapefruit juice
Heavy metals which complex with CYOSa like lead, cadium and mercury

Question 23

What is glucuronidation?

Answer 23

A glucuronic acid molecule is added to the drug by a glucuronsyl transferases

Question 24

What is sulphation?

Answer 24

Addition of a sulphur molecule to the drug by cytosolic sulphotransferase enzyme requiring a co-factor of 3’phosphoadenosine 5’phosphosulphate

Question 25

What is amino acid/peptide conjugation?

Answer 25

When a drug is combined with (typically) gylcine or glutathione via glutathione S transferases

Question 26

What is acetylation?

Answer 26

When an N-acetyltransferase adds an acetyl compound, this reaction requires an acetyl coA and is ofent used on sulphonamide drugs