Drug Metabolism

Question 1

Why is it important to understand biotransformation?

Answer 1

Is the major route of drug elimination.
Often activates/inactivates drugs
may produce toxic products
Can be variable between patients
Explains many drug interactions

Question 2

What are the two phases of biotransformation?

Answer 2

Phase 1- conversion of drug to an intermediate, through CYP enzymes (cytochrome P450)
Phase 2- addition of a larger radical, and is usually excreted in urine. Transferase enzymes associated (glucuronyl-, sulphate and acetate)

Question 3

What does CYP do?

Answer 3

metabolises 70% of drugs and are found in the gut wall and the liver

contains heme group (for oxygen, for oxidation)

Question 4

CYP1A2 (drugs, inducer and inhibitor)

Answer 4

Marker drug: theophylline, in bronchodilators

Induction: tobacco, BBQ and green veges
Inhibition: cimetidine (H2 receptor antagonsit for peptic ulcers)

Question 5

CYP2E1 (clinical relevance and inducer)

Answer 5

marker drug: ethanol (as an inducer0
Clinically seen with analgesic paracetamol to form NAPQI (dangerous metabolite)
Induction: ethanol

Question 6

CYP2C9 (adverse events and ethnicity)

Answer 6

Marker: warfarin

adverse events: bleeding

Ethnicity: 25% of caucasian people have lower amounts of CYP2C9, and 1% of Asians do.
Thus if low number of this enzyme, impaired clearance and higher risk of adverse effects.

Question 7

CYP2C19 (the clinically relevant drug, inhibitor and ethnicity and therapeutic benefits)

Answer 7

Marker drug: s-mephenytoin (phenytoin is an anticolvulsant)
Clinically relevant: Also metabolises omeprazole. People with different genotypes of the enzyme show varying results, poor metabolisers= better results

Inhibitor: Clopidogrel (a prodrug, so competes with omeprazole)

Ethnicity: 4% caucasians have low clearance and 20% of Asians do, so will show better results

Question 8

CYP2D6 (3 clinically relevant drugs, inhibitors, ethnicity)

Answer 8

Marker: debrisoquine (anti hypertensive drug)

Clincally relevant: Tricyclic anti-depressants 9 amitriptyline); beta blockers (metoprolol0; prodrug analgesics (codeine, tramadol)

Inhibitor: Fluoxetine (SSRI)

Ethnicity: 7% caucasians have low clearance, 1% asians

Question 9

CYP3A4 (clinically relevant, inhibitor, inducer)

Answer 9

Marker drug: simvastatin

Clinically relevant: statins; protease inhibitors (anti- HIV); immunosuppresant (cyclosporine)

Inhibitor: ketoconazole and grapefruit juice
Inducer: St Johns Wort

Question 10

Summary of CYP inducers vs inhibitors

Answer 10

Inducer: increase drug clearance and stimulate the enzyme to work more. eg tobacco smoke and theophylline

Inhibitor: usually competitive and reduce clearance of some drugs like grapefruit juice