Lecture 4: drug metabolism

Question 1

Biotransformations?

Answer 1

RH —> R-OH —> ROR’

oxidation followed by an addition

consist of two stages usually

1- Cytochrome P450

2- Transferases (glucuronyl-, sulphate-, acetate-)

Question 2

CYP actions? Location?

Answer 2

they act on over 70% of drugs (mainly CYP 1, 2, 3)

gut wall (good for bioavailability)

and liver (good for clearance)

Question 3

CYP 1A2

Answer 3

marker drug -Theophylline (metabolised extensively by CYP1A2)

clinically relevant drug as a bronchodilator

interactions: tobacco, green veges, BBQ = inducers

cemetidine = inhibitor

no ethnicity difference

Question 4

CYP 2E1?

Answer 4

Marker drug -ethanol (not primary metabolism for ethanol but is a maker drug)

clinically relevant drug - analgesic paracetamol = forms NAPQI which is toxic

interctions: ethanol (is an inducer)

ethnicity difference not found

Question 5

CYP 2C9

Answer 5

marker drug - s-warfarin (s-enantiomer of the raecemic mixture given)

clinically relevant = anticoagulant (warfarin)

adverse effects = lower dose and increase bleeding

25% caucasians need loer dose due to lower enz activity

1%of asainf express less activity

Question 6

CYP 2C19

Answer 6

marker drug = s-mephenytoin

clinically relevent drug = omeprazole (proton-pump inhibitor)

Therapeutic benefit: omeprazole=cure of GORD 86% in poor metabolisers, 46% in homogenous extensive metabolisers as it inhibits CYP2C19 (maybe we should be giving bigger doses…)

Drug interaction: decreased effectiveness witth clopidogrel an anti-platelet agent, when used witb omperazole

4% of caucasian and 20% asains have low clearance

Question 7

CYP2D6

Answer 7

marker drug = debrisoquine

clin rel drugs:

1. tricyclic-antidepressants (amitriptyline)
2. beta- blockers (metopralol)
3. pro drug analgesics (tramadol, codeine)

Drug interactions

1. Fluoxitine (anti-depressant)
2. quinidine (inhibitor of CYP2D6)

7% caucasian and 1% asain have low CL

Question 8

CYP 3A4

Answer 8

marker drug = simvastatin

clinically relevant drugs:

simvastatin, protease inhibitor= anti-HIV, immunosuppresant -(cyclosporine)

• enzyme induced by St John’s Wort = increases gut wall metabolism of cyclosporin = cyclosporin is less active
• enzyme inhibited by ketoconazole, grapefruit juice(particularly in gut) = rabdomyalysis - breakdown of muscle releasing myoglobin into blood = RF