Pharmokinetics ( Metabolism + Elimination)

Question 1

Where does the majority of drug metabolism take place and with what enzymes ?

Answer 1

In the liver

• using phase 1 and phase 11 enzymes.

Question 2

Phase 1 metabolism is carried out by …

Answer 2

Cytochrome P450 enzymes

Question 3

Are CYP450s generalists or specific enzymes ?

Answer 3

Generalists - they metabolise a wide range of molecules

Question 4

What sort of reactions to CYP450 catalyse ?

Answer 4

• dealkylation
• Redox reactions
• Hydroxylation reactions
• these enzymes INCREASE ionic charge of the drug molecule - now inactivating the drug - so it is eliminated directly or go onto phase 11 enzymes

Question 5

Are all drugs deactivated after phase 1 metabolism?

Answer 5

No , some pro-drugs are in fact activated by phase 1 metabolism to active species

Question 6

Give an example of a pro drug that is activated by CYP450 enzymes during phase 1 metabolism ?

Answer 6

• Codeine to Morphine

- this is a good thing , because morphine has 200 x greater affinity for opioid u receptors than codeine.

Question 7

Phase 11 metabolism is carried out by …

Answer 7

Hepatic enzymes for example conjugating enzymes

Question 8

Are phase 11 enzymes specific or generalists?

Answer 8

• they are still generalists but exhibit more rapid kinetics than phase 1 enzymes

Question 9

What type of reactions do phase 11 enzymes catalyse ?

Answer 9

• sulphation
• glutathione conjugation
• methylation
• N-acetylation
• glucorinadation
• phase 11 enzymes metabolism drugs to further increase ionic charge
• phase 11 enzymes enhances renal elimination

Question 10

How many superfamilies of cytochrome P450 are there ?

Answer 10

Three superfamilies : CYP 1 ,2 and 3

• izozyme members in each family coded by suffix : eg CYP(3)A4

Question 11

What are a few factors that affect drug metabolism ?

Answer 11

AGE -

SEX - for example alcohol metabolism is slower in women

GENERAL HEALTH : hepatic / renal disease , CVS which results in decreased functional reserve

GENETIC FACTORS : genetic polymorphism , non expression of CYP450s

Other drugs can induce / inhibit CYP450s

Question 12

Give an example of CYP450 induction

Answer 12

• CBZ ( carbamezepine) drug is an anti-epileptic drug that is metabolised by CYP3A4.
• CBZ induces CYP 3A4 - which lowers its own levels of CBZ affecting control of epilepsy. As rate of elimination will be increased and plasma levels of drug would then fall.

Question 13

Give an example of CYP450 inhibition

Answer 13

• grapefruit juice inhibits CYP 3A4
• CYP 3A4 metabolises verapamil used to treat high blood pressure
• as a result of CYP3 A 4 being inhibited ( could be either competitive or non competitive ) blood pressure could be much reduced.

Question 14

Give examples of how genetic variation can affect phase 1 metabolism

Answer 14

CYP2CP : not expressed in 1% Caucasians and 1%. Asian

• this enzyme metabolises NSAIDS, Tolubtamide , phenytoin

2) CYP2C19 : not expressed in 5% Caucasians and 30% Asians
- this enzyme metabolised omeprazole , Valium and phenytoin

Question 15

Give an example of how genetic polymorphisms can effect drug metabolism,

Answer 15

• CYP2D6 gene is highly polymorphic
• CYP2D6 variants are categorised into : poor , normal/high , ultra rapid metabolisers
• Poor metabolisers : codeine to morphine - may not experience pain relief
• ultra rapid : codeine to morphine - may lead to morphine intoxication

Question 16

Outline problems with the expression of CYP2D6 in different ethnic groups

Answer 16

• not expressed in 7% Caucasians
• hyperactive I’m 30% East Africans
• CYP2D6 metabolisers codeine into morphines and TCAS

Question 17

What is the main route of drug elimination ?

Answer 17

Through the kidneys

Question 18

What are other routes of drug elimination?

Answer 18

• bile
• lungs through vapour
• sweat
• tears
• genital secretions
• saliva
• breast milk

Question 19

How are drugs eliminated out of the kidneys ?

Answer 19

1) first goes through glomerular filteration where the unbound drug then enters bowmans capsule
2) PCT : ionised drug molecules are carried out of the blood in the body into the kidney tubules from fenestrated capillaries into PCT cells via OATs and OCTs

3) DCT : passive reabsorption of lipid soluble , unionised drugs which have been concentrated at the lumen of the tubule because water is reabsorbed back into the blood. So these lipid soluble , unionised drugs move down their concentration gradient. Whereas the lipid insoluble , ionised drugs molecules move into urine
.

Question 20

Define clearance

Answer 20

— the volume of plasma that is completely cleared of the drug per unit time

• CL is measured in ml/min or ml.min-1
• the volume is referred to Vd ( the apparent volume of distribution)

Question 21

What is the clinical relevance of clearance and vD

Answer 21

• along with the concept of Vd , clearance predicts how long drug will stay in body
• is it clinically essential for : destining dosing schedule , therapeutic regime levels , minimising ADR
• together CL and Vd provide an estimate of drug half life

Question 22

Define drug half life

Answer 22

The amount of time over which the concentration of a drug in plasma decreases to one half that initial concentration of drug

Question 23

What is t1/2 dependant on and what is the formula

Answer 23

T1/2 is dependant on Vd and CL

t1/2 = 0.693 x Vd / CL

Question 24

If CL stays the same and Vd increases , then T1/2 …..

Answer 24

Also increases

Question 25

If CL increases and Vd stays the same then t1/2 ….

Answer 25

Decreases

Question 26

What is the difference in conc of drug/time graph between normal numbers and log scale ?

Answer 26

Normal - exponential graph where concentration of drug rapidly decreases

• however on a logged scale graph , graph is linear - this is called linear elimination kinetics

Question 27

Linear elimination kinetics

Answer 27

The rate of metabolism or excretion is proportional to plasma concentration of drug( that is if there is a large functional reserve - many phase 1/11 enzymes, many OATs and OCTs)

• then the rate of metabolism will be proportional to the number of molecules occupying a catalytic sites per unit time
• for example : if the plasma concentration is 50micromoles and the rate is 10 million molecules/second …. AT 100 micro moles the rate would be 20 million molecules /second

Question 28

At what point would elimination kinetics be referred to as saturated or zero order?

Answer 28

All enzymes and carriers flatten out - no longer work

• they cannot go any faster

Question 29

At low dose of drug ,metabolism is … order which is proportional to drug dose

Answer 29

First order because as dose of drug increases , rate of metabolism also increases

Question 30

At high doses , drug metabolism is …… order that is constant and independent of drug dose

Answer 30

Zero order because there are only so many enzyme / carriers where they flatten out and cannot work any faster.

Question 31

What are problems with zero order kinetics ?

Answer 31

• drugs at or near therapeutic dose with saturation kinetics are more likely to result in toxicity as there is a fixed rate of elimination per unit time