Metabolism and clearance Lecture 17

Question 1

Describe drug elimination

Answer 1

The irreversible removal of a drug from the body

Metabolism primarily by the liver and excretion primarily by the kidney but also through expiration or through the gut

Most drugs elminated by a combination of routes

Question 2

Describe metabolism of drugs

Answer 2

Phase 1- modification

Cytochrome P450 dependent mixed-function oxidase (important group of haem containing enzymes, metabolise a wide range of different molecules)

Causes oxidation, reduction or hydrolysis, creates highly reactive compounds

Eg. Amiodarone (class 3 antidysrhythmic) causes substrate inhibition of CYP1A2 for caffeine Non-substraye inhibition by quinidine Induction by barbiturates, rifampicin, phenytoin- CYP2C9- ibuprofen

Phase 2- conjugation

Joins the reactive phase 1 metabolite with molecule to make it charged.

Groups include Glutathione, sulfate, glucuronic acid

Adding a net charge to a metabolite Aids renal clearance

Question 3

What are active metabolites?

Answer 3

Metabolites may still be Active giving either a toxic or therapeutic effect even if the drug isnt present

Eg. Morphine- converted to morphine-6-glucuronide another analgesic

Pethidine- converted to norpethidine which is epileptogenic

Prodrugs- inactive drugs administered to be converted to the active form

Question 4

Briefly describe paracetamol metabolism

Answer 4

Phase 1- N-hydroxylation by CYP2E1 or CYP1A2 or CYP2D6 to form NAPQI

Phase 2- conjugation to glutathione

In overdose conjugation cannot proceed quickly enough and NAPQI accumulates

Treated with N-acetylcystein, helps conjugation into GSH

Question 5

Describe drug elimination from the kidney

Answer 5

Charged molecules tend to be trapped in the tubules and are then excreted in the urine by 2 types of transporters

• Acid transporters- penicillin, uric acid
• Organic base transporters- pethidine and quinine

Can be competition between drugs for transporters slowing clearance Ion trapping in acidic urine

Drugs can be excreted/elminated by:

1. Renal - filtration in the glomerulus and secretion in proximal tubule
2. Hepatic - hence faecal elimination
3. Other (sweat, milk, breath)

Question 6

What is the volume of distribution

Answer 6

The volume of fluid required to contain the total amount of drug in the body at the same concentration as that present in the plasma.

Vd = D / Cp

D = amount of drug (mg) Cp = conc of drug in plasma (mg/L)

Often given in L/kg in which case you must multiply body mass prior to calculating

-Used to calculate dose required to hit target concentration

Question 7

How can you calculate renal clearance of drug X?

Answer 7

Clearance is the volume of body fluid (usaully plasma) cleared of a substance per unit time

Clearance= [X]u x Urine flow rate/ [X]p

Xu - conc of drug in urine

Xp - conc of drug in plasma

t1/2 = ln(2) x Vd / Cl

Question 8

Describe warfarin pharmocokinetics

Answer 8

Warfarin has 2 isomers (R and S) metabolised by different enzymes

R warfarin isomer is metabolised by CYP1A1, CYP1A2, CYP2C19, CYP3A4

S warfarin isomer is five times more pottent than R warfarin counterpart and is almost exclusisevly metabolised by CYP2C9