Liver function and drug metabolism

Question 1

Interaction of the liver with kidney - in terms of excretion and metabolism ?

Answer 1

Liver metabolises drug producing a metabolite.
*
( in order to be excreted drug needs to water soluble (ionised ) - so metabolic transformation required = excretable products ) - most drugs not all - some are readily excretable.

Kidney then excretes this through glomerular filtration and tubular secretion (active process )

• Age - increasing age —–> kidneys function declines ——> GFR falls ——-> active tubular secretion becomes more important in terms of secretion.

Question 2

Stages of Liver metabolism ?

Answer 2

Phase 1 - introduce a polar group e.g - OH , COOH - makes it more water soluble

• occurs in smooth endoplasmic reticulum of hepatocyte.
• reactions catalysed by cytochrome P450 enzyme (haem containing enzyme )

REACTIONS INVOLVED

1. Oxidation -
   
   1. Drug binds to oxidised for CYP450
   2. CYP450 reduced by addition electron to iron complexed within enzyme
      ( from fe3+ to fe2+)
      3. oxygen binds.
      4. Water is lost as a product
      5. Oxidised drug- CYP complex produced.
      4. The drug and oxygen leave this complex and a oxidised drug complexed produced (drug bound to o2 alone ) - drug more polar and likely to be excreted.
   3. process repeated for another another drug.

Stage 2

0 Does not involve CYP450 system

0 Conjugation of Phase 1 product with :
      - 
      Glucuronic 
      acid - most 
      common 
      - Glycine
      - Taurine
      - Sulphate

Question 3

What are the important isoforms of CYP450 enzyme ?

Answer 3

CYP3A4 ( CYP 450 3A4) - most important - Metabolises larger portion of drugs - more drugs rely on this isoform for metabolism
* enzyme inducing

These isoforms - polymorphic (many shapes - activity of CYPs differ between different people ) - IMPORTNAT AS DRUGS MAY BE METABOLISED DIFFERENTLY BTW PATIENTS.

CYP2D6 (CYP 450 2D6) - actvity does not change - not inducible

High expression ( have multiple copies )of this in Ethopian / Saudi people. This means :

1. Toxins / drug rapidly metabolised - become ineffective.
   
   • many
     antidepressants,
   • neuroleptics
2. Prodrugs that need metabolic conversion to be active form - excessively activated.
   e.g codeine
   ( codeine inactive form of morphine ) - excessive levels of morphine.

Others may have Low activity of CYP2D6

opposite of high expression
0 Antidepressant / neuroepeptics - toxic doses
0 Codeine does not work - not converted to active form
0 Beta blockers - Propranolol -may be poorly cleared - accumulate - toxic levels.

CYP2C9
* enzyme inducing

CYP2C19
* enzyme inducing

Deficiency in CYP2C19 -

0 warfarin clearance ineffective –> narrow therapeutic index —-> dosing challenging - may have to reduce dose to prevent toxicity and risk of haemorrhage.

Enzyme inducing (inducible ) - activity can be upregulated

Question 4

Drug A metabolised by CYP3A4 . Drug B induces activity of CYP3A4

What happens to conc of drug A ?

Answer 4

CYP3A4 upregulated - activity increases
Drug A rapidly metabolised and cleared from the body

Concentration of Drug A drops.
Dose no longer effective

• Drug - drug interaction

Can promote Tolerance - Dose which previously had therapeutic benefit no longer effective over time - need to increase dose. (larger and larger doses )

Question 5

What is Tolerance ?

After explain how it links to Phenobaritial /
* Link to alchol.

Answer 5

Tolerance - Dose which previously had therapeutic benefit no longer effective over time - need to increase dose. (larger and larger doses needed )

ex - Phenobarbital relies on CYP2B2 to be metabolised.

(Autoinduction )Over time - it induces 2B2 as it is being metabolised - upregulating it . SO original dose becomes ineffective and larger dose needed (upwards titration of Phenobarbital ) - over weeks

Alcohol link - Alcohol inhibits 2B2 - meaning if patient is on this high dose of Phenobarbital it will not be metabolised and excreted - toxic levels - death. - happen suddenly.

Question 6

Patient is prescribed Drug A - metabolised by CYP3A4

Drugs B inhibits CYP3A4.

What will happen to concentration of drug A.

Answer 6

Drug A poorly metabolised and cleared

Toxic doses - due to accumulation of drug.

Question 7

How do fruit interact with the isoforms ?

Answer 7

0 Grapefruit juice - CYP 3A4 inhibition

Cranberry juice - CYP 2C19 - Inhibition